EP2246333B1 - Indazole, benzisoxazole, and benzisothiazole kinase inhibitors - Google Patents

Indazole, benzisoxazole, and benzisothiazole kinase inhibitors Download PDF

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Publication number
EP2246333B1
EP2246333B1 EP10164213A EP10164213A EP2246333B1 EP 2246333 B1 EP2246333 B1 EP 2246333B1 EP 10164213 A EP10164213 A EP 10164213A EP 10164213 A EP10164213 A EP 10164213A EP 2246333 B1 EP2246333 B1 EP 2246333B1
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Prior art keywords
phenyl
amino
urea
benzisoxazol
fluoro
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EP10164213A
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German (de)
French (fr)
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EP2246333A1 (en
Inventor
Yujia Dai
Steven K. Davidsen
Anna M. Ericsson
Kresna Hartandi
Zhiqin Ji
Michael R. Michaelides
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Abbott Laboratories
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Abbott Laboratories
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Priority claimed from US10/443,254 external-priority patent/US20040235892A1/en
Priority claimed from US10/842,292 external-priority patent/US7297709B2/en
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    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions

  • the present invention relates to compounds which are useful for inhibiting protein tyrosine kinases, methods of making the compounds, compositions containing the compounds, and the compounds for use in treating diseases.
  • PTKs Protein tyrosine kinases
  • endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas).
  • inappropriate vascularization e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas.
  • the identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable.
  • the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for antiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition as well as associated disorders would be beneficial.
  • WO 02/055517 refers to to 4-arylindolinones, as well as pharmaceutical compositions thereof, capable of modulating protein kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
  • WO 00/27627 refers to aryloxime linkers in the solid-phase synthesis of 3-aminobenzisoxazoles , to a solid support bound intermediate compound that optionally can be derivatized before a cyclization and displacement procedure provides a product; to a library -and its synthesis- of polycyclic heterocycle compounds where said library contains a plurality of diverse library compounds, and to an assay kit for the identification of lead compounds of said library.
  • GB 816 382 refers to light sensitive layers for photomechanical reproduction, and particularly to the use in the preparation of such light sensitive layers of photo-sensitive diazo-derivatives of heterocyclic nitrogeneous bases.
  • WO 03/051847 refers to (1-H-indazol-3-yl)-amide derivatives as gsk-3 inhibitors.
  • WO 03/097610 refers to aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them.
  • WO 2004/010995 refers to fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of i.a. rheumatoid arthristis.
  • WO 2004/022544 refers to aminoindazole derivatives as medicines and pharmaceutical compositions containing said aminoindazole derivatives.
  • WO 03/087072 refers to a preventive and/or therapeutic agent for sicknesses associated with endothelial disorder, sepsis, severe sepsis or septic shock and sicknesses associated with signals through TLR, which comprises as an active ingredient a 3-amino-1,2-benzisothiazole compound or a derivative thereof.
  • WO 2004/062662 refers to aminoindazole derivatives and to the use thereof for the treatment of diseases that can result from abnormal kinase activity.
  • the present invention relates to compounds of formula (II) as per appended claim 1.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (II) as per appended claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention relates to a use of a compound of formula (II) as per appended claim 1, or a therapeutically acceptable salt thereof for manufacturing a medicament for inhibiting a protein kinase in a patient in recognized need of such treatment wherein the compound is to be administered to the patient in a therapeutically acceptable amount.
  • the present invention relates to a use of a compound of formula (II) as per appended claim 1, or a therapeutically acceptable salt thereof for manufacturing a medicament for treating cancer in a patient in recognized need of such treatment wherein the compound is to be administered to the patient in a therapeutically acceptable amount.
  • the present invention relates to a compound of formula (II) as per appended claim 1 for use as a protein kinase inhibitor or as an anti-cancer agent.
  • the present disclosure pertains to a compound of formula (I) or a therapeutically acceptable salt thereof, wherein
  • the present invention provides a compound of formula (II) or a therapeutically acceptable salt thereof, wherein
  • the present invention provides a compound of formula (II) wherein L is CH 2 C(O)NR 7 ; and X, R 1 , R 2 , R 3 , R 4 , R 7 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; and m, n, X, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR a R b )alkoxy, (NR a R b )alkenyl, (NR a R b )alkyl, (NR a R b )carbonylalkenyl, and (NR a R b )carbonylalkyl; and X, L, R a , R b , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula(II) wherein X is O and L, R 1 , R 2 , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy wherein the heterocyclyl is morpholinyl; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula(II) wherein X is S and L, R 1 , R 2 , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyakyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) n N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a Rb b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy wherein the heterocyclyl is morpholinyl; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (II), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a compound of formula (II), or a therapeutically acceptable salt thereof for use in inhibiting protein kinase in a patient in recognized need of such treatment by administering to the patient a therapeutically acceptable amount of said compound of formula (II), or said therapeutically acceptable salt thereof.
  • the present invention provides a compound of formula (II), or a therapeutically acceptable salt thereof for use in treating cancer in a patient in recognized need of such treatment by administering to the patient a therapeutically acceptable amount of said compound of formula (II), or said therapeutically acceptable salt thereof.
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • therapeutically acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an -NR a R b group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, frichloroacetate,trifluoroacetate, phosphate, glutamate, bicarbonate
  • -NR a R b groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • the present compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formula (II) for example, by hydrolysis in blood.
  • the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula (II), or therapeutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (II) and therapeutically acceptable salts thereof are as described above.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recepient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (II), or a therapeutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5mg to 1g, preferably 1mg to 700mg, more preferably 5mg to 100mg of a compound of formula (II), depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of an active ingredient per dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compounds of the present invention can be administered using conventional drug delivery technology, for example, intra-arterial stents.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by cumminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided.
  • Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
  • the compounds of formula (II), and therapeutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • the compounds of formula (II), and therapeutically acceptable salts thereof, may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments; creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations are preferably applied as a topical ointment or cream for use in treatments of the eye or other external tissues, for example mouth and skin.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent
  • compositions adapted for use in topical administration in the mouth include lozenges, pastilles, and mouth washes.
  • compositions adapted for use in rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for use in nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insulators.
  • compositions adapted for use in vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for use in parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of formula (II) for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (II), or a therapeutically acceptable salt thereof, and the use of at least one other cancer treatment method.
  • combination therapies according to the present invention comprise the administration of at least one other pharmaceutically active agent, preferably an anti-neoplastic agent.
  • the compound(s) of formula (II) and the other pharmaceutically active agent(s) may be administered together or separately and when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (II) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of formula (II), or therapeutically acceptable salts thereof, and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies.
  • the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent.
  • the administration in combination of a compound of formula (II), or therapeutically acceptable salts thereof, with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts of formula (II) include the following:
  • the potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide ( Z. Songyang et al., Nature. 373:536-539 ) by a test compound relative to control.
  • an exogenous substrate e.g., synthetic peptide ( Z. Songyang et al., Nature. 373:536-539 ) by a test compound relative to control.
  • the coding sequence for the human KDR intra-cellular domain was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection.
  • MOI plaque forming units per cell
  • SF-9 cells expressing (His) 6 KDR(aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1mM PMSF, 10 ⁇ g/ml aprotinin, 1 ⁇ g/ml leupeptin) to the cell pellet from 1L of cell culture.
  • the lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4°C.
  • the cell lysate was applied to a 5 ml NiCl 2 chelating sepharose column, equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCl.
  • KDR was eluted using the same buffer containing 0.25 M imidazole.
  • Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity.
  • the purified KDR was exchanged into 25mM HEPES, pH7.5, 25mM NaCl, 5 mM DTT buffer and stored at -80°C.
  • KDR KDR at IC50's between about 0.003 ⁇ M and about 40 ⁇ M.
  • Preferred compounds inhibited KDR at IC50's between about 0.003 ⁇ M and about 0.1 ⁇ M.
  • the coding sequence for the human Tie-2 intra-cellular domain was generated through PCR using cDNAs isolated from human placenta as a template. A poly-His 6 sequence was introduced at the N-terminus and this construct was cloned into transfection vector pVL 1939 at the Xba 1 and Not 1 site. Recombinant BV was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR.
  • the baculoviral expression vector pVL 1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated through PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection.
  • EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 ⁇ L) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100).
  • the baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.)
  • the nucleotide sequence encoding amino acids M(H)6 LVPR 9 S was placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619).
  • the nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cDNA libraries isolated from Jurkat immortalized T-cells. The histidine residues enabled affinity purification of the protein (vide infra).
  • the LVPR 9 S bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, enabling removal of the affinity tag from the enzyme.
  • SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours post infection.
  • SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 ⁇ g/ml leupeptin, 10 ⁇ g/ml aprotinin and 1 mM sodium orthovanadate.
  • the soluble lysate was applied to a chelating sepharose HiTrap column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. Fusion protein was eluted with 250 mM imidazole.
  • the enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.
  • Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may be commercially obtained (e.g., from Upstate Biotechnology Inc. (Saranac Lake, N.Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods.
  • Enzyme linked immunosorbent assays were used to detect and measure the presence of tyrosine kinase activity.
  • the ELISA were conducted according to known protocols which are described in, for example, Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C .
  • the disclosed protocol was adapted for determining activity with respect to a specific PTK.
  • preferred protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as non-receptor tyrosine kinases, are well within the abilities of those in the art.
  • a universal PTK substrate e.g., random copolymer of poly(Glu 4 Tyr), 20,000-50,000 MW
  • ATP typically 5 ⁇ M
  • the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl 2 , 20 mM MgCl 2 , 5 mM DTT, 0.2% BSA, 200 mM NaVO 4 under the analogous assay conditions.
  • Compounds of formulas 1-109 may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of formulas 1-109.
  • the human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • a protocol that can be used is that provided with the purchased reagents with minor modifications.
  • the reaction is carried out in a buffer consisting of 50mM Tris pH 7.5, 100mM NaCl, 1mM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10mM MgCl 2 (commercial buffer) supplemented with fresh 300 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ g/ml histone type IIIss final concentrations.
  • a reaction volume of 80 ⁇ L, containing units of enzyme is run for 20 minutes at 25 degrees C in the presence or absence of inhibitor.
  • the reaction is terminated by the addition of 120 ⁇ L of 10% acetic acid.
  • the substrate is separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75mM phosphoric acid. Counts are measured by a betacounter in the presence of liquid scintillant.
  • the catalytic subunit of PKC may be obtained commercially (Calbiochem).
  • a radioactive kinase assay is employed following a published procedure ( Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166, 1220-1227 (1990 )). Briefly, all reactions are performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, 10mM MgCl 2 , 2mM DTT, 1mM EGTA, 100 ⁇ M ATP, 8 ⁇ M peptide, 5% DMSO and 33 P ATP (8Ci/mM). Compound and enzyme are mixed in the reaction vessel and the reaction is initiated by addition of the ATP and substrate mixture.
  • the recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • reaction is carried out in a buffer consisting of 50 mM Tris pH 7.5, 1mM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl 2 (commercial buffer) supplemented with fresh 100 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ M myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity are as described for the PKC assay (vide supra).
  • Equal amounts of proteins are then precipitated by addition of cold (-20 °C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight.
  • Pellets are reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min.
  • the proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, CA) and transferred onto a nitrocellulose membrane using the Novex system.
  • the proteins After blocking with bovine serum albumin (3%), the proteins are probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 °C. After washing and incubating for 1 hour with HRP-conjugated F(ab) 2 of goat anti-rabbit or goat-anti-mouse IgG the bands are visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Heights, IL).
  • ECL emission chemiluminescience
  • This assay measures the capacity of compounds to inhibit the acute increase in uterine weight in mice which occurs in the first few hours following estrogen stimulation.
  • This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature.
  • Cullinan-Bove and Koss demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus.
  • mice All hormones can be purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to supplier instructions.
  • Vehicle components DMSO, Cremaphor EL
  • Mice (Balb/c, 8-12 weeks old) can be purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional Animal Care and Use Committee Guidelines.
  • Day 1 Balb/c mice are given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG).
  • Day 3 Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.
  • mice are randomized and divided into groups of 5-10. Test compounds are administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Vehicle control group receive vehicle only and two groups are left untreated.
  • the difference between wet and blotted weights is taken as the fluid content of the uterus.
  • Mean fluid content of treated groups is compared to untreated or vehicle treated groups. Significance is determined by Student's test. Non-stimulated control group is used to monitor estradiol response.
  • Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization.
  • the Matrigel neovascularization model involves the formation of new blood vessels within a clear marble of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528 ; Anat. Rec. (1997), 249(1), 63-73 ; Int. J. Cancer (1995), 63(5), 694-701 ; Vasc. Biol. (1995), 15(11), 1857-6 ).
  • the model preferably runs over 3-4 days and endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors.
  • the model may alternatively employ bFGF or HGF as the stimulus.
  • the compounds of the present invention may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system.
  • diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (e.g,.
  • kidney rejection, graft versus host disease benign and neoplastic proliferative diseases
  • human cancers such as lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma, and diseases involving inappropriate vascularization (for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings).
  • diseases vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings.
  • Such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).
  • the compounds of the invention may be useful in the treatment of pulmonary hypertension, particularly in patients with thromboembolic disease ( J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73 ).
  • This invention is intended to encompass compounds having formula (II) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • Scheme 1 shows the synthesis of compounds of formula (4).
  • Compounds of formula (3) can be reacted with an appropriately substituted isocyanate (R 6 NCO) to provide compounds of formula (4).
  • R 6 NCO isocyanate
  • Examples of solvents used in these reactions include THF, dichloromethane, and MTBE.
  • the reaction is typically conducted at a temperature of about 0 °C to about 25°C for about 1 hour to about 14 hours.
  • Compounds of formula (Ia) can be prepared following the procedures described in Scheme 2.
  • Compounds of formula (5) can be converted to compounds of formula (6) by treatment with hydrazine.
  • solvents include n-butanol, ethanol, n-pentanol, and n-hexanol. The reaction is typically conducted at about 80°C to about 120°C for about 2 to about 12 hours.
  • Conversion of compounds of formula (6) to compounds of formula (Ia) can be accomplished by treatment with compounds of formula (7) in the presence of a palladium catalyst and a base.
  • Representative palladium catalysts include Pd(PPh 3 ) 4 , Pd(o-tol 3 P) 2 Cl 2 , PdCl 2 (dppf), and PdCl 2 (dppf)CH 2 Cl 2 .
  • bases include sodium carbonate, cesium carbonate, and potassium carbonate.
  • Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60°C and about 130°C (optionally in a microwave for about 5 to about 25 minutes) for about 4 to about 24 hours.
  • compounds of formula (8) can be converted to compounds of formula (9) by treatment with NBS in the presence of a radical initiator such as benzoyl peroxide AIBN.
  • a radical initiator such as benzoyl peroxide AIBN.
  • solvents used in this reaction include CCl 4 , benzene, and CHCl 3 .
  • the reaction is typically conducted at about 60 to about 80°C for about 4 to about 48 hours.
  • Compounds of formula ( 9 ) can be converted to compounds of formula ( 5a ) by treatment with a nucleophile (Z) (for example, an amine or an alcohol).
  • a nucleophile for example, an amine or an alcohol
  • solvents used in these reactions include THF, DMF, NMP, and DME.
  • the reaction is typically conducted at about 20°C to about 60 °C for about 12 to about 24 hours.
  • Scheme 4 shows the synthesis of compounds of formula ( Ib ).
  • Compounds of formula ( 6 ) (prepared by the methods described in Scheme 2) can be converted to compounds of formula ( 10 ) by treatment with an appropriately substituted borane or other organometallic reagent such as a stannane or organozinc reagent in the presence of a palladium catalyst and optionally a base.
  • Representative palladium catalysts include Pd(PPh 3 ) 4 , Pd(o-tol 3 P) 2 Cl 2 , PdCl 2 (dppf), and PdCl 2 (dppf) ⁇ CH 2 Cl 2 .
  • bases include sodium carbonate, cesium carbonate, and potassium carbonate.
  • Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60 °C and about 130 °C for about 4 to about 24 hours.
  • Compounds of formula ( 10 ) can be converted to compounds of formula ( Ib ) by treatment with the appropriately substituted electrophile to generate L (i.e., an isocyanate of formula R 6 NCO).
  • L i.e., an isocyanate of formula R 6 NCO.
  • solvents include dichloromethane, chloroform, THF, DMF, and MTBE. The reaction is typically conducted at about -5°C to about 25 °C for about 12 to about 24 hours.
  • compounds of formula ( 11 ) can be reacted with the compound of formula ( 12 ), a palladium catalyst, and potassium acetate, then treated with compounds of formula ( 6 ) in the presence of a palladium catalyst and a base to provide compounds of formula ( Ib ).
  • Representative palladium catalysts include Pd(PPh 3 ) 4 , Pd(o-tol 3 P) 2 Cl 2 , PdCl 2 (dppf), and PdCl 2 (dppf) ⁇ CH 2 Cl 2 .
  • bases include sodium carbonate, cesium carbonate, and potassium carbonate.
  • Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof.
  • Compounds of formula ( Id ) can be prepared as described in Scheme 7.
  • Compounds of formula ( 16 ) can be converted to compounds of formula ( 17 ) using the conditions described in Schemes 2 and 4.
  • Compounds of formula ( 17 ) can be converted to compounds of formula ( 18 ) (where L 2 is an alkenyl group and R d is (NR a R b )carbonyl or alkoxycarbonyl) by treatment with a palladium catalyst and a base such as triethylamine or diisopropylethylamine.
  • solvents include THF and 1,4-dioxane.
  • the reaction is typically conducted at about 80 to about 150°C for about 30 minutes to about 6 hours.
  • Scheme 8 shows the synthesis of compounds of formula ( Ie ).
  • Compounds of formula ( 21 ) (where Q is Br or I) can be reacted with the compound of formula ( 22 ) in the presence of potassium tert-butoxide to provide compounds of formula ( 23 ).
  • solvents used in this reaction include DMF, DME, and NMP. The reaction is typically conducted at about 20 °C to about 35°C for about 15 minutes to about 12 hours.
  • Examples 1-94; 117-260 and 332-380 are comparative.
  • Example 1A 60mg, 0.24 mmol
  • Example 1B 103mg, 0.29 mmol
  • Na 2 CO 3 64mg, 0.6 mmol
  • DME 8 mL
  • water 2 mL
  • Pd(PPh 3 ) 4 14mg, 0.012 mmol
  • the mixture was purged with bubbling nitrogen for 2 minutes, heated to 80-90 °C for about 18 hours, cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the crude product by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile/0.1 % aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the product by preparative HPLC using the conditions described in Example 3.
  • Example 1A 80mg, 0.32 mmol
  • Example 5A 144mg, 0.39 mmol
  • Na 2 CO 3 58mg
  • DME 3 mL
  • water 1 mL
  • Pd(PPh 3 ) 4 (19 mg, 0.0161 mmol
  • the vial was capped and heated to 160°C for 10 minutes with stirring in a Smith Synthesizer microwave oven (at 300W).
  • the reaction was concentrated and the residue was purified by HPLC using the conditions in Example 3 to provide 63 mg of the desired product as the trifluoroacetate salt.
  • the desired product was prepared by substituting I-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example 1C.
  • the desired product was prepared by substituting 1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example 1C.
  • Example 15A (19.3g, 69.1 mmol) in thionyl chloride (60 mL) was heated to 80 °C for 3 hours, cooled to room temperature, and concentrated. The residue was dissolved in THF (100 mL), cooled to 0 °C, treated with concentrated NH 4 OH (80 mL), stirred at room temperature for about 18 hours, and concentrated. The concentrate was suspended in water and filtered. The filter cake was washed with water and dried to provide 18.67g of the desired product. MS (CI/NH 3 ) m/e 280 (M+H) + .
  • Example 15B A solution of Example 15B (18.6g, 66.7 mmol) in DMF (190 mL) was treated dropwise with thionyl chloride (24mL, 333 mmol), heated to 115°C for 16 hours, cooled to room temperature, poured into ice, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide 12.35g (71% yield) of the desired product. MS (CI/NH 3 ) m/e 279 (M+NH 4 ) + .
  • Example 15D A solution of Example 15D (710mg, 2.09 mmol) and morpholine (0.546 mL, 6.25 mmol) in DMF (8 mL) was stirred at room temperature overnight, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated to provide 0.71g of the desired product.
  • R f 0.4 (ethyl acetate).
  • Example 15E 2-fluoro-6-iodobenzonitrile in Example 1A.
  • R f 0.18 (ethyl acetate).
  • Example 15F The desired product was prepared by substituting Example 15F and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline for Example 1A and 1B, respectively, in Example 1C.
  • Example 15G A solution of Example 15G (50mg, 0.155 mmol) in dichloromethane was cooled to 0 °C, treated with 1-fluoro-3-isocyanatobenzene (0.021 mL), stirred at room temperature overnight, and concentrated.
  • the concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide 24mg of the desired product as the trifluoroacetate salt.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-3-isocyanatobenzene in Example 15H.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 1-fluoro-3-isocyanatobenzene in Example 15H.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for 1-fluoro-3-isocyanatobenzene in Example 15H.
  • Example 15F A solution of Example 15F (80mg, 0.22 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea (108mg, 0.268 mmol) in toluene (2 mL) and ethanol (1.5 mL) was treated with a solution of Na 2 CO 3 (58mg) in water (1mL), degassed with nitrogen for 2 minutes, treated with Pd(PPh 3 ) 4 (13mg, 0.011 mmol), and degassed with nitrogen for another 2 minutes.
  • Na 2 CO 3 58mg
  • Pd(PPh 3 ) 4 13mg, 0.011 mmol
  • the vial was capped and heated to 140-150°C for 8-10 minutes with stirring in a Smith Synthesizer microwave oven (at 300W).
  • the reaction was poured into water and extracted three times with ethyl acetate.
  • the combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by HPLC using the conditions in Example 15H to provide 55mg of the desired product as the trifluoroacetate salt.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-[2-fluoro-5-(trifluoromethyl)phenyl]-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared by substituting 1,2-difluoro-4-iodobenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
  • Example 26B The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 26B The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 26B The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 26B The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 3-isocyanatobenzonitrile for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 31A and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 31A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • Example 34A The desired product was prepared by substituting Example 34A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example 1A and 1B, respectively, in Example 1C.
  • the desired product was prepared by substituting 1-isocyanato-3-methylbenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • the resulting product was purifed by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide the desired product.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-(trifluoromethyl)benzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-2-isocyanato-4-methylbenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • Example 44A A mixture of Example 44A (100mg, 0.31 mmol), bis(pinacolato)diboron (86mg, 0.33 mmol), Pd(dppf)Cl 2 (10mg) and potassium acetate (270mg) in DMF (3 mL) was heated to 80 °C for 2 hours, treated with Example 1A (64mg, 0.24 mmol), Pd(dppf)Cl 2 (6mg), Na 2 CO 3 (78mg), and water (1mL), heated to 80°C for 18 hours, cooled to room temperature, and concentrated. The concentrate was purified by preparative HPLC using the conditions described in Example 15H to provide 27mg of the desired product as the trifuoroacetate salt.
  • Example 44B The desired product was prepared by substituting methyl (4-bromophenyl)acetate and K 3 PO 4 for Example 44A and Na 2 CO 3 , respectively, in Example 44B. Additionally the reaction was carried our under anhydrous conditions. MS (ESI(+)) m/e 304 (M+H) + .
  • Example 53A 140mg was stirred at room temperature for 2 hours and adjusted to pH 3 with 10% HCl. The resulting precipitate was collected by filtration to provide 108mg of the desired product. MS (ESI(+)) m/e 268 (M+H) + .
  • Example 53B A mixture of Example 53B (40mg, 015mmol), diisopropylethylamine (0.078 mL, 0.45 mmol), TBTU (57mg, 0.18 mmol), and aniline in THF (1 mL) was stirred for 18 hours at room temperature and concentrated. The residue was purified by preparative HPLC using the conditions described in Example 15H to provide 15mg of the desired product as the trifluoroacetate salt.
  • the desired product was prepared by substituting 3-(trifluoromethyl)aniline for aniline in Example 53C, then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 411.
  • the desired product was prepared by substituting 2-fluoro-4-iodo-1-methoxybenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
  • Example 15H The desired product was prepared by substituting Example 58B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 15H The desired product was prepared by substituting Example 58B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 58B The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-isocyanato-3-ethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 2-fluoro-4-isocyanato-1-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 58B and 1-chloro-3-isocyanatobenzene were prepared as the trifluoroacetate salt by substituting Example 58B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • MS (ESI(+)) m/e 408 (M+H) + ;
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 68A A mixture of Example 68A (104mg, 0.39 mmol), 1-bromo-2-methoxyethane (0.088 mL) and K 2 CO 3 (163mg) in acetone (3 mL) was heated to 60°C for 18 hours, cooled to room temperature, and partitioned between diethyl ether and water. The extract was dried (MgSO 4 ), filtered, and concentrated to provide 122mg of the desired product MS (ESI(+)) m/e 334 (M+H) + .
  • Example 15 The desired product was prepared by substituting Example 68C and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15, then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 68A A mixture of Example 68A (250mg, 0.95 mmol), 2-(4-morpholinyl)ethanol (0.19 mL) and triphenylphosphine on resin (630mg, 3mmol/g, 1.9 mmol) in THF (5 mL) was treated with DEAD (0.179 mL) and stirred at room temperature for about 18 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified twice by flash column chromatography on silica gel, first eluting with 5% methanol/dichloromethane then with 50% ethyl acetate/hexanes to provide 180mg of the desired product. MS (ESI(+)) m/e 377 (M+H) + .
  • N (4- ⁇ 3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl)phenyl)-N'-(3-methylphenyl)urea
  • Example 15H The desired product was prepared by substituting Example 75B and 1-isocyanate-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-ethyl-3-isocyanatabenzene for Example 15G and 1-fluoro-3 - isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared by substituting 4-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile in Example 1A.
  • Example 84A The desired product was prepared by substituting Example 84A and 4-nitrophenylboronic acid for Example 1A and Example 1B, respectively, in Example 1C.
  • Example 84B A mixture of Example 84B (165mg), N,N-dimethylacrylamide (0.102 mL), triethylamine (0.207 mL), and Pd(o-tol 3 P) 2 Cl 2 (30mg) in THF (2 mL) in a sealed tube was heated in a Smith Synthesizer microwave oven (at 300W) to 150 °C and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide 163mg of the desired product. MS (ESI(+)) m/e 352 (M+H) + .
  • Example 84C A solution of Example 84C (113mg, 0.32 mmol) in a mixture of ethanol (1 mL), methanol (1 mL), and THF (1 mL) was treated with iron powder (144mg) and NH 4 Cl (17mg), heated to 85 °C for 4 hours, cooled to room temperature, and filtered. The filtrate was partitioned between water and ethyl acetate and the organic phase was dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 75mg of the desired product. MS (ESI(+)) m/e 322 (M+H) + .
  • Example 84D The desired product was prepared as the trifluoroacetate salt by substituting Example 84D and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • MS (ESI(+)) m/e 455 (M+H) + ;
  • Example 15H The desired product was prepared by substituting Example 84D and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 15H The desired product was prepared by substituting Example 84D and 1-isocyanato-3-(trifluromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared by substituting 1-(2-hydroxyethyl)-2-pyrrolidinone for 2-(4-morpholinyl)ethanol in Example 75A-B. MS (ESI(+)) m/e 352 (M+H) + .
  • the desired product was prepared by substituting Example 34A and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-m-tolyl-acetamide for Example 1A and Example 1B, respectively, in Example 53 C.
  • the crude product was purified by preparative HPLC using the conditions described in Example 3 to provide the desired product as the trifluoroacetate salt.
  • Example 91A and 1-chloro-3-isocyanatobenzene were prepared as the trifluoroacetate salt by substituting Example 91A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 95A was prepared by substituting Example 95A for Example 1A in Example 1C.
  • the desired product was prepared by substituting 1-isocyanato-2-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Example 1B.
  • Example 95A and Example 96A were prepared by substituting Example 95A and Example 96A for Example 1A and Example 1B, respectively, in Example 1C.
  • Example 95A and Example 5A were prepared by substituting Example 95A and Example 5A for Example 1A and Example 1B, respectively, in Example 1C.
  • the desired product was prepared by substituting 1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Example 1B.
  • Example 95A and Example 98A were prepared by substituting Example 95A and Example 98A for Example 1A and Example 1B, respectively, in Example 1C.
  • the desired product was prepared by substituting 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Example 1B.
  • Example 95A and Example 99A were prepared by substituting Example 95A and Example 99A for Example 1A and Example 1B, respectively, in Example 1C.
  • the desired product was prepared by substituting 2-fluoro-4-iodo-1-methoxybenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
  • Example 95A The desired product was prepared by substituting Example 1 00A for 2-bromo-6-fluorobenzonitrile in Example 95A.
  • Example 100B was prepared by substituting Example 100B for Example 15F in Example 15G.
  • Example 15H The desired product was prepared by substituting Example 100C and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 100C and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 100C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • the desired product was prepared by substituting Example 100C and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 100C and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • the desired product was prepared by substituting Example 15E for 2-bromo-6-fluorobenzonitrile in Example 95A.
  • Example 105A for Example 15F in Example 15G.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-isocyanato-3,5-dimethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-isocyanato-3-phenoxybenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-bromo-3 - isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • the desired product was prepared by substituting Example 75A for 2-bromo-6-fluorobenzonitrile in Example 95A.
  • Example 113A was prepared by substituting Example 113A for Example 15F in Example 15G.
  • Example 15H The desired product was prepared by substituting Example 113B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 113B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 113B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 113B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 68C and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and I-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 119A The desired product was prepared by substituting Example 119A and 1-fluoro-2-isocyanato-4-methylbenzene for 2-fluoro-6-iodobenzonitrile and 1-isocyanato-3-methylbenzene, respectively, in Examples 1A-1C.
  • Example 119B (90mg) and a 1:1:1 mixture of 3N HCl/methanol/THF (3 mL) was heated to 50°C for 3 hours, concentrated to half its original volume, and partitioned between saturated NaHCO 3 and ethyl acetate. The organic extract was dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromcthane to provide 30mg of the desired product.
  • Example 121A for Example 15G in Example 15H.
  • Example 121B The desired product was prepared as the trifluoroacetate salt by substituting Example 121B for Example 119B in Example 120, then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 15H The desired product was prepared by substituting Example 121A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 122A was prepared as the trifluoroacetate salt by substituting Example 122A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 15H The desired product was prepared by substituting Example 121A and 1-ethyl-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 123A was prepared as the trifluoroacetate salt by substituting Example 123A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 15H The desired product was prepared by substituting Example 121A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 124A was prepared as the trifluoroacetate salt by substituting Example 124A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • MS (ESI(+)) m/e 446 (M+H) + ;
  • Example 15H The desired product was prepared by substituting Example 121A and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 125A was prepared as the trifluoroacetate salt by substituting Example 125A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 121A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 126A The desired product was prepared as the trifluoroacetate salt by substituting Example 126A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • MS (ESI(-)) m/e 392 (M-H) - ;
  • Example 15H The desired product was prepared by substituting Example 121A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 127A was prepared as the trifluoroacetate salt by substituting Example 127A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 15H The desired product was prepared by substituting Example 121A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product can be prepared by substituting Example 128A for Example 119B in Example 120.
  • the desired product was prepared by substituting 2-(1-pyrrolidinyl)ethanol for 2-(4-morpholinyl)ethanol in Examples 75A and 75B.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3 - isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared by substituting 2-(diethylamino)ethanol for 2-(4-morpholinyl)ethanol in Examples 75A and 75B.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared by substituting Example 145A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 145A and 1-chloro-3-isocyanatobenzene were prepared by substituting Example 145A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared by substituting Example 145A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 145A and 1-isocyanato-3-(trifluoromethyl)benzene were prepared by substituting Example 145A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 149A A mixture of Example 149A (219mg, 0.62 mmmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (190mg, 0.75 mmol), potassium acetate (183mg), and PdCl 2 (dppf)CH 2 Cl 2 (15mg) in DMF (6 mL) was degassed then heated to 80 °C for 2 hours. The mixture was used directly in the next reaction.
  • Example 149B and PdCl 2 (dpp) ⁇ CH 2 Cl 2 were prepared by substituting Example 149B and PdCl 2 (dpp) ⁇ CH 2 Cl 2 for Example 1B and Pd(PPh 3 ) 4 , respectively, in Example 1C. Additionally, DMF was used in place of DME.
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 26A A -78 °C solution of Example 26A (5.0g, 18.9 mmol) in THF was treated with LDA (2M in hexanes, 11.5 mL, 22.6 mmol), stirred for 1 hour at -78 °C, treated with methyl formate (2.34 mL, 37.8 mmol), stirred at -78 °C for 30 minutes, warmed to 0 °C for I hour, quenched with saturated NH 4 Cl and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated.
  • Example 152A 2-fluoro-6-iodobenzonitrile in Example 1A.
  • R f 0.53 (ethyl acetate).
  • Example 152B 50mg, 0.16 mmol
  • Example 5A 66mg, 0.18 mmol
  • Pd(PPh 3 ) 4 9mg, 0.008 mmol
  • Na 2 CO 3 43mg, 0.4 mmol
  • toluene 2 mL
  • ethanol 1 mL
  • water 1 mL
  • the samples were cooled using 40 psi pressurized air.
  • the mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40mL/min to provide 26mg of the desired product as the trifluoroacetate salt.
  • the desired product was prepared as the trifluoroacetate salt by substituting N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 152C.
  • the desired product was prepared as the trifluoroacetate salt by substituting N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 152C.
  • Example 152A 350mg, 1.18 mmol in dichloromethane (10 mL) was treated with triethylamine (0.25 mL, 1.78 mmol) and methanesulfonyl chloride (0.1 mL, 1.3 mmol), stirred at 0 °C for 1 hour, treated with diethylamine (0.245 mL, 2.37 mmol), and overnight at room temperature.
  • the mixture was partitioned between 1N NaOH and dichloromethane and the organic extract was dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 3:1 hexanes/ethyl acetate to provide 0.263g of the desired product.
  • Example 157B and Example 98A were prepared as the trifluoroacetate salt by substituting Example 157B and Example 98A for Example 152B and Example 5A, respectively, in Example 152C.
  • Example 152B The desired product was prepared as the trifluoroacetate salt by substituting Example 157B and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 152B and Example 5A, respectively, in Example 152C.
  • Example 157B and Example 1B were prepared as the trifluoroacetate salt by substituting Example 157B and Example 1B for Example 152B and Example 5A, respectively, in Example 152C.
  • the desired product was prepared by substituting 3-pyridinol for morpholine in Examples 15E-F.
  • Example 161A and Example 98A were prepared by substituting Example 161A and Example 98A for Example 152B and Example 5A, respectively, in Example 152C then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 1A A mixture of Example 1A (1.09g) and phthalic anhydride (0.75g) in dioxane (15 mL) was stirred overnight at 120 °C and concentrated. The residue was triturated from diethyl ether (15 mL) to provide 0.51g of the desired product. MS (ESI(+)) m/e 388 (M+H) + .
  • Example 162A A mixture of Example 162A (100mg), 4-(2-chloroethyl)morpholine (48mg), and Na 2 CO 3 (82mg) in DMF (5 mL) was heated overnight at 80 °C, cooled to room temperature, and partitioned between 1N HCl and ethyl acetate. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The extract was dried (MgSO 4 ), filtered, and concentrated to provide 45mg of the desired product. MS (ESI(+)) m/e 503 (M+H) + .
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and 1-chloro-3-isocyanatobenzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H.

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Abstract

Compounds having the formula are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

Description

    Technical Field
  • The present invention relates to compounds which are useful for inhibiting protein tyrosine kinases, methods of making the compounds, compositions containing the compounds, and the compounds for use in treating diseases.
    • Background of the Invention
  • Protein tyrosine kinases (PTKs) are enzymes which catalyse the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes themselves, acts as a molecular switch regulating cell proliferation, activation, or differentiation. Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas).
  • The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for antiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition as well as associated disorders would be beneficial.
  • WO 02/055517 refers to to 4-arylindolinones, as well as pharmaceutical compositions thereof, capable of modulating protein kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
  • WO 00/27627 refers to aryloxime linkers in the solid-phase synthesis of 3-aminobenzisoxazoles , to a solid support bound intermediate compound that optionally can be derivatized before a cyclization and displacement procedure provides a product; to a library -and its synthesis- of polycyclic heterocycle compounds where said library contains a plurality of diverse library compounds, and to an assay kit for the identification of lead compounds of said library.
  • GB 816 382 refers to light sensitive layers for photomechanical reproduction, and particularly to the use in the preparation of such light sensitive layers of photo-sensitive diazo-derivatives of heterocyclic nitrogeneous bases.
  • WO 03/051847 refers to (1-H-indazol-3-yl)-amide derivatives as gsk-3 inhibitors.
  • WO 03/097610 refers to aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them.
  • WO 2004/010995 refers to fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of i.a. rheumatoid arthristis.
  • WO 2004/022544 refers to aminoindazole derivatives as medicines and pharmaceutical compositions containing said aminoindazole derivatives.
  • WO 03/087072 refers to a preventive and/or therapeutic agent for sicknesses associated with endothelial disorder, sepsis, severe sepsis or septic shock and sicknesses associated with signals through TLR, which comprises as an active ingredient a 3-amino-1,2-benzisothiazole compound or a derivative thereof.
  • WO 2004/062662 refers to aminoindazole derivatives and to the use thereof for the treatment of diseases that can result from abnormal kinase activity.
    • Summary of the Invention
  • The present invention relates to compounds of formula (II) as per appended claim 1.
  • The present invention relates to a pharmaceutical composition comprising a compound of formula (II) as per appended claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • The present invention relates to a use of a compound of formula (II) as per appended claim 1, or a therapeutically acceptable salt thereof for manufacturing a medicament for inhibiting a protein kinase in a patient in recognized need of such treatment wherein the compound is to be administered to the patient in a therapeutically acceptable amount.
  • The present invention relates to a use of a compound of formula (II) as per appended claim 1, or a therapeutically acceptable salt thereof for manufacturing a medicament for treating cancer in a patient in recognized need of such treatment wherein the compound is to be administered to the patient in a therapeutically acceptable amount.
  • The present invention relates to a compound of formula (II) as per appended claim 1 for use as a protein kinase inhibitor or as an anti-cancer agent.
    • Detailed Description of the Invention
  • The present disclosure pertains to a compound of formula (I)
    Figure imgb0001
     or a therapeutically acceptable salt thereof, wherein
    • A is selected from the group consisting of indolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl;
    • X is selected from the group consisting of O, S, and NR9;
    • R1 and R2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NR8Rb)alkenyl, (NRaRb)alkyl, (NRaRb)alkynyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl;
    • R3, R4, and R5 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, and LR6; provided that at least two of R3, R4, and R5 are other than LR6;
    • L is selected from the group consisting of (CH2)mN(R7)C(O)N(R8)(CH2)n and CH2C(O)NR7, wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to A;
    • R6 is selected from the group consisting of hydrogen, aryl, cycloalkyl, heterocyclyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl;
    • R7 and R8 are independently selected from the group consising of hydrogen and alkyl;
    • R9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl;
    • Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl; and
    • Rc and Rd are independently selected from the group consisting of hydrogen, alkyl alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
  • In its principle embodiment the present invention provides a compound of formula (II)
    Figure imgb0002
     or a therapeutically acceptable salt thereof, wherein
    • X is selected from the group consisting of O and S;
    • R1 and R2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl;
    • R3 and R4 are independently selected from the group consisting of hydrogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy;
    • L is selected from the group consisting of (CH2)mN(R7)C(O)N(R8)(CH2)n and CH2C(O)NR7, wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to the ring substituted with R3 and R4;
    • R7 and R8 are independently selected from the group consising of hydrogen and alkyl;
    • R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl alkoxycarbonyl, alkyl, aryloxy, arylalkyl carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd;
    • Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; and
    • Ro and Rd are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
    wherein
    the aryl is a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group,
    wherein said aryl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, (NRcRd)alkyl, and oxo;
    wherein the second aryl group, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl is optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;
    the heterocyclyl is a monocyclic, bicyclic, or tricyclic ring system wherein one or more rings is a four-, five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
    wherein said heterocyclyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, (NRcRd)alkyl, and oxo;
    wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl is further optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.
    The cycloalkyl is a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms,
    wherein said cycloalkyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo.
  • In another embodiment, the present invention provides a compound of formula (II) wherein L is CH2C(O)NR7; and X, R1, R2, R3, R4, R7, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula (II) wherein L is (CH2)mN(R7)C(O)N(R8)(CH2)n; and m, n, X, R1, R2, R3, R4, R7, R8, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula (II) wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl; and X, L, Ra, Rb, R3, R4, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula(II) wherein X is O and L, R1, R2, R3, R4, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is O; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; and m, n, R1, R2, R3, R4, R7, R8, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is O; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is O; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is O; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is heterocyclylalkoxy; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is O; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is heterocyclylalkoxy wherein the heterocyclyl is morpholinyl; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is O; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula(II) wherein X is S and L, R1, R2, R3, R4, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; and m, n, R1, R2, R3, R4, R7, R8, R10, and R11 are as defined in formula (II).
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyakyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2, R3, R4, R7, and R8 are hydrogen; and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)nN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is heterocyclylalkoxy; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRbb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is heterocyclylalkoxy wherein the heterocyclyl is morpholinyl; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH2)mN(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl.
  • In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (II), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • In another embodiment, the present invention provides a compound of formula (II), or a therapeutically acceptable salt thereof for use in inhibiting protein kinase in a patient in recognized need of such treatment by administering to the patient a therapeutically acceptable amount of said compound of formula (II), or said therapeutically acceptable salt thereof.
  • In another embodiment, the present invention provides a compound of formula (II), or a therapeutically acceptable salt thereof for use in treating cancer in a patient in recognized need of such treatment by administering to the patient a therapeutically acceptable amount of said compound of formula (II), or said therapeutically acceptable salt thereof.
    • Definitions
  • All publications, issued patents, and patent applications cited herein are hereby incorporated by reference.
  • As used herein, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.
  • As used in the present specification the following terms have the meanings indicated:
    • The term "alkenyl," as used herein, refers to a straight or branched chain group of one to six carbon atoms containing at least one carbon-carbon double bond.
    • The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
    • The term "alkoxyalkoxy," as used herein, refers to an alkoxy group attached to the parent molecular moiety through another alkoxy group.
    • The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with at least one alkoxy group.
    • The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
    • The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six carbon atoms. Preferred alkyl groups of the present invention are of one to three carbon atoms. Most preferred alkyl groups are methyl and ethyl.
    • The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
    • The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
    • The term "aryl," as used herein, refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group. Bicyclic fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Aryl groups include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, (NRcRd)alkyl, and oxo; wherein the second aryl group, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.
    • The term "arylalkyl," as used herein, refers to an alkyl group substituted with at least one aryl group.
    • The term "arylcarbonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
    • The term "arylalkoxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
    • The term "aryloxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an oxygen atom.
    • The term "aryloxyalkyl," as used herein, refers to an aryloxy group attached to the parent molecular moiety through an alkyl group.
    • The term "arylsulfonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.
    • The term "carbonyl," as used herein, refers to -C(O)-.
    • The term "carboxy," as used herein, refers to -CO2H.
    • The term "cyano," as used herein, refers to -CN.
    • The term "cycloalkenyl," as used herein, refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, wherein each five-membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine-to ten-membered ring has one to four double bonds. Examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.
    • The term "cycloalkyl," as used herein, refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo [3..1.1]heptyl, and adamantyl.
    • The cycloalkyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo.
    • The terms "halo," and "halogen," as used herein, refer to F, Cl, Br, and I.
    • The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
    • The term "haloalkyl," as used herein, refers to an alkyl group substituted by one; two, three, or four halogen atoms.
    • The term "haloalkylsulfonyl," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through a sulfonyl group.
    • The term "heterocyclyl," as used herein, represents a monocyclic, bicyclic, or tricyclic ring system wherein one or more rings is a four-, five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen and sulfur. The 3- and 4-membered rings have no double bonds, the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, and trithiane. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to phenyl ring, a monocyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group, as defined herein, or another monocyclic heterocyclyl ring system. Representative examples of bicyclic ring systems include but are not limited to, benzimidazole, benzothiazole, benzothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, dihydrobenzimidazole, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine. Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to a phenyl ring, a monocyclic cyloalkyl group as defined herein, a monocyclic cycloalkenyl group as defined herein, or another monocyclic heterocyclyl ring system. Representative examples of tricyclic ring systems include, but are not limited to, acridine, carbazole, carboline, dibenzofuran, dibenzothiophene, naphthofuran, naphthothiophene, oxanthrene, phenarine, phenoxathiin, phenoxazine, phenothiazine, thianthrene, thioxanthene, and xanthene. Heterocyclyl groups can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group.
    • The heterocyclyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, (NRcRd)alkyl, and oxo; wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.
    • The term "heterocyclylalkenyl," as used herein, refers to an alkenyl group substituted with at least one heterocyclyl group.
    • The term "heterocyclylalkoxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group.
    • The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with at least one heterocyclyl group.
    • The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an oxygen atom.
    • The term "heterocyclyloxyalkyl," as used herein, refers to an alkyl group substituted with at least one heterocyclyloxy group.
    • The term "heterocyclylsulfonyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a sulfonyl group.
    • The term "hydroxy," as used herein, refers to -OH.
    • The term "hydroxyalkoxy," as used herein, refers to a hydroxy group attached to the parent molecular moiety through an alkoxy group.
    • The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with at least one hydroxy group.
    • The term "nitro," as used herein, refers to -NO2.
    • The term "-NRaRb," as used herein, represents two groups, Ra and Rb, which are attached to the parent molecular moiety through a nitrogen atom. Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl, wherein the aryl, the aryl part of the arylalkyl and the arylcarbonyl, the heterocyclyl, the heterocyclyl part of the heterocyclylalkyl and the heterocyclylsulfonyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.
    • The term "(NRaRb)alkenyl," as used herein, represents an alkenyl group substituted with at least one -NRaRb group.
    • The term "(NRaRb)alkoxy," as used herein, represents an -NRaRb group attached to the parent molecular moiety through an alkoxy group.
    • The term "(NRaRb)alkyl," as used herein, represents an alkyl group substituted with at least one -NRaRb group.
    • The term "(NRaRb)alkynyl," as used herein, represents an alkynyl group substituted with at least one -NRaRb group.
    • The term "(NRaRb)carbonyl," as used herein, represents an (NRaRb) group attached to the parent molecular moiety through a carbonyl group.
    • The term "(NRaRb)carbonylalkenyl," as used herein, represents an alkenyl group substituted with at least one (NRaRb)carbonyl group.
    • The term "(NRaRb)carbonylalkyl," as used herein, represents an alkyl group substituted with at least one (NRaRb)carbonyl group.
    • The term "-NRcRd," as used herein, represents two groups, Rc and Rd, which are attached to the parent molecular moiety through a nitrogen atom. Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein the aryl, the aryl part of the arylalkyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.
    • The term "(NRcRd)alkyl," as used herein, represents an alkyl group substituted with at least one -NRcRd group.
    • The term "oxo," as used herein, refers to =O.
    • The term "sulfonyl," as used herein, refers to -SO2.
  • The compounds of the present invention can exist as therapeutically acceptable salts. The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an -NRaRb group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, frichloroacetate,trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, -NRaRb groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • The present compounds can also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug," refers to compounds which are rapidly transformed in vivo to parent compounds of formula (II) for example, by hydrolysis in blood.
  • When it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (II), as well as therapeutically acceptable salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula (II), or therapeutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (II) and therapeutically acceptable salts thereof are as described above. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recepient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (II), or a therapeutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5mg to 1g, preferably 1mg to 700mg, more preferably 5mg to 100mg of a compound of formula (II), depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of an active ingredient per dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). In addition, compounds of the present invention can be administered using conventional drug delivery technology, for example, intra-arterial stents.
  • Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by cumminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an altenative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
  • Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
  • The compounds of formula (II), and therapeutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • The compounds of formula (II), and therapeutically acceptable salts thereof, may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments; creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • The formulations are preferably applied as a topical ointment or cream for use in treatments of the eye or other external tissues, for example mouth and skin. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in oil base.
  • Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent
  • Pharmaceutical formulations adapted for use in topical administration in the mouth include lozenges, pastilles, and mouth washes.
  • Pharmaceutical formulations adapted for use in rectal administration may be presented as suppositories or as enemas.
  • Pharmaceutical formulations adapted for use in nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical formulations adapted for use in administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insulators.
  • Pharmaceutical formulations adapted for use in vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • Pharmaceutical formulations adapted for use in parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of formula (II) for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • The compounds of the present invention and therapeutically acceptable salts thereof, may be employed alone or in combination with other therapeutic agents for use in the treatment of the above-mentioned conditions. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal, or antibody agents is envisaged as well as combination with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (II), or a therapeutically acceptable salt thereof, and the use of at least one other cancer treatment method. Preferably, combination therapies according to the present invention comprise the administration of at least one other pharmaceutically active agent, preferably an anti-neoplastic agent. The compound(s) of formula (II) and the other pharmaceutically active agent(s) may be administered together or separately and when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (II) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • The compounds of formula (II), or therapeutically acceptable salts thereof, and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies. In one embodiment, the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent. The administration in combination of a compound of formula (II), or therapeutically acceptable salts thereof, with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts of formula (II) include the following:
    1. (1) cell cycle specific anti-neoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuidine; antimetabolites such as allopurinol, fluduxabine, methotrexate, cladrabine, cytarabine, mercaptopurine, and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, topotecan, CPT-11, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;
    2. (2) cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anti-tumor antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttainomycin, and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and
    3. (3) other chemotherapeutic agents including, but not limited to, anti-estrogens such as tomixefen, toremifene, raloxifene, droloxifene, and iodoxyfene; progesterogens such as megastrol acetate; aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagonists such as goserelin acetate and luprolide, testosterone 5α-dihydroreductase inhibitors such as finasteride; metalloproteinase inhibitors such as marimastat; antiprogestogens; urokinase plasminogen activator receptor function inhibitors; growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR and TIE-2 (other than those VEGFR and TIE-2 inhibitors described in the present invention)); and other tyrosine kinase inhibitors such as inhibitors of CDK2 and CDK4 inhibitors.
    Determination of Biological Activity
  • The in vitro potency of compounds in inhibiting these protein kinases may be determined by the procedures detailed below.
  • The potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by a test compound relative to control.
    • KDR Tyrosine Kinase Production Using Baculovirus System:
  • The coding sequence for the human KDR intra-cellular domain (aa789-1354) was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection.
    • Purification of KDR
  • SF-9 cells expressing (His)6KDR(aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1mM PMSF, 10µg/ml aprotinin, 1 µg/ml leupeptin) to the cell pellet from 1L of cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4°C. The cell lysate was applied to a 5 ml NiCl2 chelating sepharose column, equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCl. KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity. The purified KDR was exchanged into 25mM HEPES, pH7.5, 25mM NaCl, 5 mM DTT buffer and stored at -80°C.
  • Compounds of the present invention inhibited KDR at IC50's between about 0.003 µM and about 40 µM. Preferred compounds inhibited KDR at IC50's between about 0.003 µM and about 0.1 µM.
    • Human Tie-2 Kinase Production and Purification
  • The coding sequence for the human Tie-2 intra-cellular domain (aa775-1124) was generated through PCR using cDNAs isolated from human placenta as a template. A poly-His6 sequence was introduced at the N-terminus and this construct was cloned into transfection vector pVL 1939 at the Xba 1 and Not 1 site. Recombinant BV was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR.
    • Human Flt-1 Tyrosine Kinase Production and Purification
  • The baculoviral expression vector pVL 1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated through PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection.
    • EGFR Tyrosine Kinase Source
  • EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 µL) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100).
    • Expression of ZAP70
  • The baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.) The nucleotide sequence encoding amino acids M(H)6 LVPR9S was placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619). The nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cDNA libraries isolated from Jurkat immortalized T-cells. The histidine residues enabled affinity purification of the protein (vide infra). The LVPR9S bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, enabling removal of the affinity tag from the enzyme. SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours post infection.
    • Extraction and purification of ZAP70
  • SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 µg/ml leupeptin, 10 µg/ml aprotinin and 1 mM sodium orthovanadate. The soluble lysate was applied to a chelating sepharose HiTrap column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. Fusion protein was eluted with 250 mM imidazole. The enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.
    • Protein kinase source
  • Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may be commercially obtained (e.g., from Upstate Biotechnology Inc. (Saranac Lake, N.Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods.
    • Enzyme Linked Immunosorbent Assay (ELISA) For PTKs
  • Enzyme linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. The ELISA were conducted according to known protocols which are described in, for example, Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C.
  • The disclosed protocol was adapted for determining activity with respect to a specific PTK. For example, preferred protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as non-receptor tyrosine kinases, are well within the abilities of those in the art. For purposes of determining inhibitor selectivity, a universal PTK substrate (e.g., random copolymer of poly(Glu4 Tyr), 20,000-50,000 MW) was employed together with ATP (typically 5 µM) at concentrations approximately twice the apparent Km in the assay.
  • The following procedure was used to assay the inhibitory effect of compounds of this invention on KDR, Flt-1, Flt-4, Tie-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, hck, Blk, Csk, Src, Lyn, fgr, Fyn and ZAP70 tyrosine kinase activity:
    • Buffers and Solutions:
    • PGTPoly (Glu,Tyr) 4:1
    • Store powder at -20 °C. Dissolve powder in phosphate buffered saline (PBS) for 50mg/ml solution. Store 1ml aliquots at -20 °C. When making plates dilute to 250µg/ml in Gibco PBS.
    • Reaction Buffer: 100mM Hepes, 20mM MgCl2, 4mM MnCl2, 5mM DTT, 0.02%BSA, 200µM NaVO4, pH 7.10
    • ATP: Store aliquots of 100mM at -20 °C. Dilute to 20µM in water
    • Washing Buffer: PBS with 0.1% Tween 20
    • Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in PBS
    • TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue Substrate from Neogen
    • Stop Solution: 1M Phosphoric Acid
    Procedure
    1. 1. Plate Preparation:
      • Dilute PGT stock (50mg/ml, frozen) in PBS to a 250µg/ml. Add 125µl per well of Corning modified flat bottom high affinity ELISA plates (combing #25805-96). Add 125 µl PBS to blank wells. Cover with sealing tape and incubate overnight 37°C. Wash 1x with 250µl washing buffer and dry for about 2hrs in 37°C dry incubator.
      • Store coated plates in sealed bag at 4°C until used.
    2. 2. Tyrosine Kinase Reaction:
      • Prepare inhibitor solutions at a 4x concentration in 20% DMSO in water.
      • Prepare reaction buffer
      • Prepare enzyme solution so that desired units are in 50µl, e.g. for KDR make to 1 ng/µl for a total of 50ng per well in the reactions. Store on ice.
      • Make 4x ATP solution to 20µM from 100mM stock in water. Store on ice
      • Add 50µl of the enzyme solution per well (typically 5-50 ng enzyme/well depending on the specific activity of the kinase)
      • Add 25µl 4x inhibitor
      • Add 25µl 4x ATP for inhibitor assay
      • Incubate for 10 minutes at room temperature
      • Stop reaction by adding 50µl 0.05N HCl per well
      • Wash plate
      **Final Concentrations for Reaction: 5µM ATP, 5% DMSO
    3. 3. Antibody Binding
      • Dilute 1mg/ml aliquot of PY20-HRP (Pierce) antibody(a phosphotyrosine antibody)to 50ng/ml in 0.1% BSA in PBS by a 2 step dilution (100x, then 200x)
      • Add 100µl Ab per well. Incubate 1 hr at room temp. Incubate 1hr at 4 °C.
      • Wash 4x plate
    4. 4. Color reaction
      • Prepare TMB substrate and add 100µl per well
      • Monitor OD at 650nm until 0.6 is reached
      • Stop with 1M Phosphoric acid. Shake on plate reader.
      • Read OD immediately at 450nm
  • Optimal incubation times and enzyme reaction conditions vary slightly with enzyme preparations and are determined empirically for each lot.
  • For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl2, 20 mM MgCl2, 5 mM DTT, 0.2% BSA, 200 mM NaVO4 under the analogous assay conditions.
  • Compounds of formulas 1-109 may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of formulas 1-109.
    • Cdc2 source
  • The human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.
    • Cdc2 Assay
  • A protocol that can be used is that provided with the purchased reagents with minor modifications. In brief, the reaction is carried out in a buffer consisting of 50mM Tris pH 7.5, 100mM NaCl, 1mM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10mM MgCl2 (commercial buffer) supplemented with fresh 300 µM ATP (31 µCi/ml) and 30 µg/ml histone type IIIss final concentrations. A reaction volume of 80µL, containing units of enzyme, is run for 20 minutes at 25 degrees C in the presence or absence of inhibitor. The reaction is terminated by the addition of 120µL of 10% acetic acid. The substrate is separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75mM phosphoric acid. Counts are measured by a betacounter in the presence of liquid scintillant.
    • PKC kinase source
  • The catalytic subunit of PKC may be obtained commercially (Calbiochem).
    • PKC kinase assay
  • A radioactive kinase assay is employed following a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166, 1220-1227 (1990)). Briefly, all reactions are performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, 10mM MgCl2, 2mM DTT, 1mM EGTA, 100 µM ATP, 8 µM peptide, 5% DMSO and 33P ATP (8Ci/mM). Compound and enzyme are mixed in the reaction vessel and the reaction is initiated by addition of the ATP and substrate mixture. Following termination of the reaction by the addition of 10 µL stop buffer (5 mM ATP in 75mM phosphoric acid), a portion of the mixture is spotted on phosphocellulose filters. The spotted samples are washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. Incorporation of radiolabel is quantified by liquid scintillation counting.
    • Erk2 enzyme source
  • The recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods.
    • Erk2 enzyme assay
  • In brief, the reaction is carried out in a buffer consisting of 50 mM Tris pH 7.5, 1mM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl2 (commercial buffer) supplemented with fresh 100 µM ATP (31 µCi/ml) and 30µM myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity are as described for the PKC assay (vide supra).
    • Cellular Receptor PTK Assays
  • The following cellular assay was used to determine the level of activity and effect of the different compounds of the present invention on KDR/VEGFR2. Similar receptor PTK assays employing a specific ligand stimulus can be designed along the same lines for other tyrosine kinases using techniques well known in the art.
  • VEGF-Induced KDR Phosphorylation in Human Umbilical Vein Endothelial Cells (HUVEC) as Measured by Western Blots:
    1. 1. HUVEC cells (from pooled donors) can be purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer directions. Only early passages (3-8) are used for this assay. Cells are cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using complete EBM media (Clonetics).
    2. 2. For evaluating a compound's inhibitory activity, cells are trypsinized and seeded at 0.5-1.0 x 105 cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA).
    3. 3. 3-4 days after seeding, plates are typically 90-100% confluent. Medium is removed from all the wells, cells are rinsed with 5-10ml of PBS and incubated 18-24h with 5ml of EBM base media with no supplements added (i.e., serum starvation).
    4. 4. Serial dilutions of inhibitors are added in 1ml of EBM media (25µM, 5µM, or 1µM final concentration to cells and incubated for one hour at 37 °C. Human recombinant VEGF165 (R & D Systems) is then added to all the wells in 2 ml of EBM medium at a final concentration of 50ng/ml and incubated at 37°C for 10 minutes. Control cells untreated or treated with VEGF only are used to assess background phosphorylation and phosphorylation induction by VEGF.
  • All wells are then rinsed with 5-10ml of cold PBS containing 1mM Sodium Orthovanadate (Sigma) and cells are lysed and scraped in 200µl of RIPA buffer (50mM Tris-HCl) pH7, 150mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1mM EDTA) containing protease inhibitors (PMSF 1mM, aprotinin 1µg/ml, pepstatin 1µg/ml, leupeptin 1µg/ml, Na vanadate 1mM, Na fluoride 1mM) and 1µg/ml of Dnase (all chemicals from Sigma Chemical Company, St Louis, MO). The lysate is spun at 14,000 rpm for 30min, to eliminate nuclei.
  • Equal amounts of proteins are then precipitated by addition of cold (-20 °C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. Pellets are reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min. The proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, CA) and transferred onto a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), the proteins are probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 °C. After washing and incubating for 1 hour with HRP-conjugated F(ab)2 of goat anti-rabbit or goat-anti-mouse IgG the bands are visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Heights, IL).
    • In vivo Uterine Edema Model
  • This assay measures the capacity of compounds to inhibit the acute increase in uterine weight in mice which occurs in the first few hours following estrogen stimulation. This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993), 133:829-837) demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus. These results have been confirmed by the use of neutralizing monoclonal antibody to VEGF which significantly reduced the acute increase in uterine weight following estrogen stimulation ( WO 97/42187 ). Hence, this system can serve as a model for in vivo inhibition of VEGF signalling and the associated hyperpermeability and edema.
  • Materials: All hormones can be purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to supplier instructions. Vehicle components (DMSO, Cremaphor EL) can be purchased from Sigma (St. Louis, MO). Mice (Balb/c, 8-12 weeks old) can be purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional Animal Care and Use Committee Guidelines.
    Method:
    Day 1: Balb/c mice are given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG).
    Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.
    Day 4: Mice are randomized and divided into groups of 5-10. Test compounds are administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Vehicle control group receive vehicle only and two groups are left untreated.
  • Thirty minutes later, experimental, vehicle and 1 of the untreated groups are given an i.p. injection of 17 -estradiol (500 mg/kg). After 2-3 hours, the animals are sacrificed by CO2 inhalation. Following a midline incision, each uterus was isolated and removed by cutting just below the cervix and at the junctions of the uterus and oviducts. Fat and connective tissue were removed with care not to disturb the integrity of the uterus prior to weighing (wet weight). Uteri are blotted to remove fluid by pressing between two sheets of filter paper with a one liter glass bottle filled with water. Uteri are weighed following blotting (blotted weight). The difference between wet and blotted weights is taken as the fluid content of the uterus. Mean fluid content of treated groups is compared to untreated or vehicle treated groups. Significance is determined by Student's test. Non-stimulated control group is used to monitor estradiol response.
  • Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization. The Matrigel neovascularization model involves the formation of new blood vessels within a clear marble of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vasc. Biol. (1995), 15(11), 1857-6). The model preferably runs over 3-4 days and endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors. The model may alternatively employ bFGF or HGF as the stimulus.
  • The compounds of the present invention may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system. Such diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (e.g,. kidney rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancers such as lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma, and diseases involving inappropriate vascularization (for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings). Such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS). In addition, the compounds of the invention may be useful in the treatment of pulmonary hypertension, particularly in patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73).
    • Synthetic Methods
  • Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: AIBN for 2,2'-azobis(2-methylpropionitrile); THF for tetrahydrofuran; MTBE for methyl tert-butyl ether, PPh3 for triphenylphosphine; o-tol3P for tri-o-tolylphosphine; dppf for diphenylphosphinoferrocene; DMF for N,N-dimethylformamide; DME for 1,2-dimethoxyethane; NBS for N-bromosuccinimide; NMP for N-methylpyrrolidinone; DMSO for dimethylsulfoxide; LDA for lithium diisopropylamide; TFA for trifluoroacetic acid; min for minutes; TBTU for O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate; and DEAD for diethyl azodicarboxylate.
  • The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of ordinary skill in the art. The groups A, X, R1, R2, R3, R4, R5, and R6 are as defined above unless otherwise noted below.
  • This invention is intended to encompass compounds having formula (II) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
    Figure imgb0003
  • Scheme 1 shows the synthesis of compounds of formula (4). Compounds of formula (3) can be reacted with an appropriately substituted isocyanate (R6NCO) to provide compounds of formula (4). Examples of solvents used in these reactions include THF, dichloromethane, and MTBE. The reaction is typically conducted at a temperature of about 0 °C to about 25°C for about 1 hour to about 14 hours.
    Figure imgb0004
  • Compounds of formula (Ia) can be prepared following the procedures described in Scheme 2. Compounds of formula (5) can be converted to compounds of formula (6) by treatment with hydrazine. Examples of solvents include n-butanol, ethanol, n-pentanol, and n-hexanol. The reaction is typically conducted at about 80°C to about 120°C for about 2 to about 12 hours. Compounds of formula (6) where R9 is hydrogen can be converted to compounds of formula (6) where R9 is alkenyl, alkoxyalkyl, alkyl, heterocyclylalkyl, hydroxyalkyl, or (NRaRb)alkyl by treatment with the appropriately substituted alkylating agent in the presence of a base under conditions known to those of ordinary skill in the art.
  • Conversion of compounds of formula (6) to compounds of formula (Ia) can be accomplished by treatment with compounds of formula (7) in the presence of a palladium catalyst and a base. Representative palladium catalysts include Pd(PPh3)4, Pd(o-tol3P)2Cl2, PdCl2(dppf), and PdCl2(dppf)CH2Cl2. Examples of bases include sodium carbonate, cesium carbonate, and potassium carbonate. Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60°C and about 130°C (optionally in a microwave for about 5 to about 25 minutes) for about 4 to about 24 hours.
    Figure imgb0005
  • As shown in Scheme 3, compounds of formula (8) can be converted to compounds of formula (9) by treatment with NBS in the presence of a radical initiator such as benzoyl peroxide AIBN. Examples of solvents used in this reaction include CCl4, benzene, and CHCl3. The reaction is typically conducted at about 60 to about 80°C for about 4 to about 48 hours.
  • Compounds of formula (9) can be converted to compounds of formula (5a) by treatment with a nucleophile (Z) (for example, an amine or an alcohol). Examples of solvents used in these reactions include THF, DMF, NMP, and DME. The reaction is typically conducted at about 20°C to about 60 °C for about 12 to about 24 hours.
  • Conversion of compounds of formula (5a) to compounds of formula (6a) can be accomplished by the methods described in Scheme 2.
    Figure imgb0006
  • Scheme 4 shows the synthesis of compounds of formula (Ib). Compounds of formula (6) (prepared by the methods described in Scheme 2) can be converted to compounds of formula (10) by treatment with an appropriately substituted borane or other organometallic reagent such as a stannane or organozinc reagent in the presence of a palladium catalyst and optionally a base. Representative palladium catalysts include Pd(PPh3)4, Pd(o-tol3P)2Cl2, PdCl2(dppf), and PdCl2(dppf)·CH2Cl2. Examples of bases include sodium carbonate, cesium carbonate, and potassium carbonate. Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60 °C and about 130 °C for about 4 to about 24 hours.
  • Compounds of formula (10) can be converted to compounds of formula (Ib) by treatment with the appropriately substituted electrophile to generate L (i.e., an isocyanate of formula R6NCO). Examples of solvents include dichloromethane, chloroform, THF, DMF, and MTBE. The reaction is typically conducted at about -5°C to about 25 °C for about 12 to about 24 hours.
    Figure imgb0007
  • As shown in Scheme 5, compounds of formula (11) can be reacted with the compound of formula (12), a palladium catalyst, and potassium acetate, then treated with compounds of formula (6) in the presence of a palladium catalyst and a base to provide compounds of formula (Ib). Representative palladium catalysts include Pd(PPh3)4, Pd(o-tol3P)2Cl2, PdCl2(dppf), and PdCl2(dppf)·CH2Cl2. Examples of bases include sodium carbonate, cesium carbonate, and potassium carbonate. Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60°C and about 130°C for about 4 to about 24 hours.
    Figure imgb0008
     The synthesis of compounds of formula (Ic) is shown in Scheme 6. Compounds of formula (13) can be reacted with the compound of formula (12) then with compounds of formula (6) using the conditions described in Scheme 5 to provide compounds of formula (14). Compounds of formula (14) can be hydrolyzed to compounds of formula (15) using conditions known to those of ordinary skill in the art (i.e., KOH). Compounds of formula (15) can be converted to compounds of formula (Ic) by treatment with an appropriately substituted amine in the presence of a coupling agent under conditions known to those of ordinary skill in the art.
    Figure imgb0009
  • Compounds of formula (Id) can be prepared as described in Scheme 7. Compounds of formula (16) can be converted to compounds of formula (17) using the conditions described in Schemes 2 and 4. Compounds of formula (17) can be converted to compounds of formula (18) (where L2 is an alkenyl group and Rd is (NRaRb)carbonyl or alkoxycarbonyl) by treatment with a palladium catalyst and a base such as triethylamine or diisopropylethylamine. Examples of solvents include THF and 1,4-dioxane. The reaction is typically conducted at about 80 to about 150°C for about 30 minutes to about 6 hours.
  • Conversion of compounds of formula (18) to compounds of formula (19) can be accomplished by methods known to those of ordinary skill in the art. Compounds of formula (19) can be converted to compounds of formula (Id) by the methods described in Scheme 4.
    Figure imgb0010
  • Scheme 8 shows the synthesis of compounds of formula (Ie). Compounds of formula (21) (where Q is Br or I) can be reacted with the compound of formula (22) in the presence of potassium tert-butoxide to provide compounds of formula (23). Examples of solvents used in this reaction include DMF, DME, and NMP. The reaction is typically conducted at about 20 °C to about 35°C for about 15 minutes to about 12 hours.
  • Compounds of formula (23) can be coupled with compounds of formula (24) using the conditions described in Schemes 2, 4, and 7 to provide compounds of formula (Ie).
  • The present invention will now be described in connection with certain preferred embodiments. Thus, the following examples, which include preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.
  • Compounds of the invention were named by ACD/ChemSketch version 5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada).
  • In the following, Examples 1-94; 117-260 and 332-380 are comparative.
    • Example 1 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea Example 1A 4-iodo-1H-indazol-3-amine
  • A mixture of 2-fluoro-6-iodobenzonitile (2g, 8.1 mmol) and hydrazine hydrate (4 mL) in n-butanol (40 mL) was heated to 105-110°C for 5 hours, cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 1.88g of the desired product. Rf = 0.25 (5% methanol/dichloromethane).
    • Example 1B N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
  • A 0 °C mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.03g, 23 mmol) and 1-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF (90 mL) was stirred at room temperature for 1 hour, concentrated, suspended in acetonitrile, and filtered. The filter cake was dried to provide 8.09g of the desired product.
    • Example 1C N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • A mixture of Example 1A (60mg, 0.24 mmol), Example 1B (103mg, 0.29 mmol) and Na2CO3 (64mg, 0.6 mmol) under a nitrogen atmosphere was treated with DME (8 mL), water (2 mL), and Pd(PPh3)4 (14mg, 0.012 mmol). The mixture was purged with bubbling nitrogen for 2 minutes, heated to 80-90 °C for about 18 hours, cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide 56mg (66% yield) of the desired product. MS (ESI(+)) m/e 358 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.33 (s, 2H), 6.76-6.83 (m, 2H), 7.17 (t, J=7.80 Hz, 1H), 7.23-7.28 (m, 3H), 7.32 (s, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.79 (s, 1H), 11.70 (s, 1H).
    • Example 2 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3,5-dimethoxyphenyl)urea
  • The desired product was prepared by substituting 1-isocyanato-3,5-dimethoxybenzene for 1-isocyanato-3-methylbenzene in Examples 1B-C. 1H NMR (300 MHz, DMSO-d6) δ 3.73 (s, 6H), 4.33 (s, 2H), 6.15 (t, J=2.20 Hz, 1H), 6.70 (d, J=2.03 Hz, 2H), 6.78 (dd, J=5.76, 2.37 Hz, 1H), 7.22-7.31 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.58 (d, J=8.81 Hz, 2H), 8.73 (s, 1H), 8.78 (s, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 404 (M+H)+.
    • Example 3 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the crude product by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7µm particle size) using a gradient of 10% to 100% acetonitrile/0.1 % aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min. 1H NMR (300 MHz, DMSO-d6) δ 6.89 (dd, J=6.44, 1.70 Hz, 1H), 7.03 (m, 1H), 7.28-7.38 (m, 4H), 7.42 (d, J=8.81 Hz, 2H), 7.61 (d, J=8.82 Hz, 2H), 7.74 (m, 1H), 9.00 (s, 1H), 9.03 (s, 1H); MS (ESI(+)) m/e 378 (M+H)+; Anal. calcd. for C20H16CIN5O·CF3CO2H: C, 52.76; H, 3.62; N, 13.98. Found: C, 52.40; H, 3.50; N, 13.86.
    • Example 4 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the product by preparative HPLC using the conditions described in Example 3. 1H NMR (300 MHz, DMSO-d6) δ 6.86 (dd, J=6.10, 2.03 Hz, 1H), 7.29-7.35 (m, 3H), 7.42 (d, J=8.81 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H), 7.58-7.65 (m, 3H), 8.05 (s, 1H), 9.01 (s, 1H), 9.16 (s, 1H); MS (ESI(+)) m/e 412 (M+H)+; Anal. calcd. for C21H16F3N5O·0.7CF3CO2H: C, 54.77; H, 3.43; N, 14.26. Found: C, 54.64; H, 3.32; N, 14.12.
    • Example 5 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 5A N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
  • A 0 °C mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.28 mmol) and 1-fluoro-2-isocyanato-4-methylbenzene (0.297 mL, 2.28 mmol) in dichloromethane (15 mL) was allowed to gradually warm to room temperature and stirred overnight. The resulting suspension was diluted with hexanes resulting in the formation of more precipitate, which was collected by filtration to provide 0.68g of the desired product. MS (ESI(+)) m/e 370.7 (M+H)+.
    • Example 5B N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • A mixture of Example 1A (80mg, 0.32 mmol), Example 5A (144mg, 0.39 mmol) and Na2CO3 (58mg) in DME (3 mL) and water (1 mL) was degassed with nitrogen for 2 minutes, treated with Pd(PPh3)4 (19 mg, 0.0161 mmol), and degassed with nitrogen for another 2 minutes. The vial was capped and heated to 160°C for 10 minutes with stirring in a Smith Synthesizer microwave oven (at 300W). The reaction was concentrated and the residue was purified by HPLC using the conditions in Example 3 to provide 63 mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 6.78-6.85 (m, 1H), 6.87 (dd, J=6.10, 1.70 Hz, 1H), 7.12 (dd, J=11.53, 8.48 Hz, 1H), 7.30-7.39 (m, 2H), 7.42 (d, J=8.81 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 2.37 Hz, 1H), 8.54 (d, J=2.71 Hz, 1H), 9.23 (s, 1H); MS (ESI(+)) m/e 376 (M+H)+; Anal calcd. for C21H18FN5O·0.8CF3CO2H: C, 58.17; H, 4.06; N, 15.01. Found: C, 58.17; H, 4.29; N, 15.12.
    • Example 6 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting I-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.79 (dd, J=5.26, 2.54 Hz, 1H), 7.24-7.3 (m, 2H), 7.42 (m, 3H), 7.52 (m, 1H), 7.61 (d, J=8.48 Hz, 2H), 8.65 (dd, J=7.29, 2.20 Hz, 1H), 8.96 (d, J=3.05 Hz, 1H), 9.32 (s, 1H), 11.72 (s, 1H); MS (ESI(+)) m/e 430 (M+H)+.
    • Example 7 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-bromo-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-d6) δ 6.87 (dd, J=6.10, 1.70 Hz, 1H), 7.13-7.18 (m, 1H), 7.25 (t, J=7.97 Hz, 1H), 7.31-7.26 (m, 3H), 7.42 (d, J=8.82 Hz, 2H), 7.61 (d, J=8.48 Hz, 2H), 7.88 (t, J=1.86 Hz, 1H), 8.99 (s, 1H); MS (ESI(-)) m/e 420, 422 (M-H)-.
    • Example 8 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-bromo-4-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 2-bromo-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 6.88 (dd, J=6.10, 1.70 Hz, 1H), 7.25-7.50 (m, 7H), 7.61 (d, J=8.48 Hz, 2H), 8.85 (s, 1H), 8.93 (s, 1H); MS (ESI(-)) m/e 434, 435 (M-H)-.
    • Example 9 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-ethyl-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, J=7.63 Hz, 3H), 2.58 (q, J=7.68 Hz, 2H), 6.81-6.88 (m, 2H), 7.19 (t, J=7.80 Hz, 1H), 7.25-7.36 (m, 4H), 7.40 (d, J=8.48 Hz, 2H), 7.60 (d, J=8.81 Hz, 2H), 8.70 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 372 (M+H)+.
    • Example 10 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared by substituting isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.78 (dd, J=5.42, 2.37 Hz, 1H), 6.98 (t, J=7.29 Hz, 1H), 7.28 (m, 4H), 7.39 (d, J=8.81 Hz, 2H), 7.48 (d, J=7.46 Hz, 2H), 7.59 (d, J=8.82 Hz, 2H), 8.72 (s, 1H), 8.81 (s, 1H), 11.70 (s, 1H); MS (ESI(+)) m/e 344 (M+H)+.
    • Example 11 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea
  • The desired product was prepared by substituting 2-fluoro-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 2.17 (s, 3H), 4.33 (s, 2H), 6.78 (dd, J=5.42, 2.71 Hz, 1H), 7.05 (dd, J=8.14, 2.03 Hz, 1H), 7.17 (t, J=8.65 Hz, 1H), 7.23-7.30 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.45 (dd, J=12.54, 2.03 Hz, 1H), 7.58 (d, J=8.81 Hz, 2H), 8.84 (s, 2H), 11.70 (s, 1H); MS ESI(+)) m/e 376 (M+H)+.
    • Example 12 N-[4-(3-amino-1H-inda-zol-4-yl)phenyl]-N'-(2-fluorophenyl)urea
  • The desired product was prepared by substituting 1-fluoro-2-isocyanatobenzene for 1-isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.79 (dd, J=5.42, 2.71 Hz, 1H), 6.97-7.06 (m, 1H), 7.16 (t, J=7.63 Hz, 1H), 7.22-7.30 (m, 3H), 7.41 (d, J=8.48 Hz, 2H), 7.60 (d, J=8.48Hz, 2H), 8.18 (m, 1H), 8.61 (d, J=2.37 Hz, 1H), 9.22 (s, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 362 (M+H)+.
    • Example 13 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea
  • The desired product was prepared by substituting 1-fluoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.78 (dd, J=5.43, 2.37 Hz, 1H), 7.13 (t, J=8.99 Hz, 2H), 7.22-7.29 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.49 (m, 2H), 7.59 (d, J=8.82 Hz, 2H), 8.80 (d, J=15.60 Hz, 2H), 11.70 (s, 1H); MS (ESI(+)) 362 (M+H)+.
    • Example 14 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting 1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.75-6.83 (m, 2H), 7.15 (m, 1H), 7.23-7.36 (m, 3H), 7.40 (d, J=8.48 Hz, 2H), 7.52 (m, 1H), 7.59 (d, J=8.48 Hz, 2H), 8.89 (s, 1H), 8.97 (s, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 362 (M+H)+.
    • Example 15 N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-fluorophenyl)urea Example 15A 2-fluoro-6-iodo-3-methylbenzoic acid
  • A -78 °C solution of 2-fluoro-4-iodo-1-methylbenzene (25g, 105.9 mmol) in THF (200 mL) was treated dropwise with LDA (2M solution in THF, 58.5 mL, 116 mmol), stirred at -78 °C for 1 hour, treated with excess powdered dry ice, stirred at -78 °C for 30 minutes, and warmed to room temperature gradually over about 18 hours. The mixture was concentrated and the residue was partitioned between 4N NaOH and diethyl ether. The aqueous phase was adjusted to pH 2 with 2N HCl and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 19.4g (66% yield) of the desired product. MS (ESI(+)) m/e 279 (M+H)+.
    • Example 15B 2-fluoro-6-iodo-3-methylbenzamide
  • A solution of Example 15A (19.3g, 69.1 mmol) in thionyl chloride (60 mL) was heated to 80 °C for 3 hours, cooled to room temperature, and concentrated. The residue was dissolved in THF (100 mL), cooled to 0 °C, treated with concentrated NH4OH (80 mL), stirred at room temperature for about 18 hours, and concentrated. The concentrate was suspended in water and filtered. The filter cake was washed with water and dried to provide 18.67g of the desired product. MS (CI/NH3) m/e 280 (M+H)+.
    • Example 15C 2-fluoro-6-iodo-3-methylbenzonitrile
  • A solution of Example 15B (18.6g, 66.7 mmol) in DMF (190 mL) was treated dropwise with thionyl chloride (24mL, 333 mmol), heated to 115°C for 16 hours, cooled to room temperature, poured into ice, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide 12.35g (71% yield) of the desired product. MS (CI/NH3) m/e 279 (M+NH4)+.
    • Example 15D 3-(bromomethyl)-2-fluoro-6-iodobenzonitrile
  • A mixture of Example 15C (8.0g, 30.6 mmol), NBS (6.54g, 36.78 mmol), and benzoyl peroxide (0.5g ) in CCl4 (100 mL) was heated to reflux for 36 hours during which time additional NBS (9g) and benzoyl peroxide(1.5g) was added in 3 portions. The suspension was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide 4.83g (46% yield) of the desired product. Rf= 0.27 (20% ethyl acetate/hexanes).
    • Example 15E 2-fluoro-6-iodo-3-(4-morpholinylinethyl)benzonitrile
  • A solution of Example 15D (710mg, 2.09 mmol) and morpholine (0.546 mL, 6.25 mmol) in DMF (8 mL) was stirred at room temperature overnight, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 0.71g of the desired product. Rf= 0.4 (ethyl acetate).
    • Example 15F 4-iodo-7-(4-morpholinylmethyl)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 15E for 2-fluoro-6-iodobenzonitrile in Example 1A. Rf = 0.18 (ethyl acetate).
    • Example 15G 4-(4-aminophenyl)-7-(4-morpholinylmethyl)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 15F and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline for Example 1A and 1B, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 2.42 (d, J=4.07 Hz, 4H), 3.58 (m, 4H), 3.65 (s, 2H), 4.36 (s, 2H), 5.24 (s, 2H), 6.66 (dd, J=7.80, 4.41 Hz, 3H), 7.12 (m, 3H), 11.45 (s, 1H); MS (ESI(+)) m/e 324 (M+H)+.
    • Example 15H N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3 -fluorophenyl)urea
  • A solution of Example 15G (50mg, 0.155 mmol) in dichloromethane was cooled to 0 °C, treated with 1-fluoro-3-isocyanatobenzene (0.021 mL), stirred at room temperature overnight, and concentrated. The concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7µm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide 24mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.79 (m, 1H), 6.92 (d, J=7.12 Hz, 1H), 7.16 (m, 1H), 7.32 (m, 1H), 7.42 (m, 3H), 7.52 (m, 1H), 7.63 (d, J=8.81 Hz, 2H), 9.12 (s, 1H), 9.16 (s, 1H); MS (ESI(+)) m/e 461 (M+H)+.
    • Example 16 N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-3-isocyanatobenzene in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.80 (d, J=7.12 Hz, 1H), 6.92 (d, J=7.12 Hz, 1H), 7.17 (t, J=7.80 Hz, 2H), 7.27 (d, J =7.23Hz, 1H), 7.32 (s, 1H), 7.42 (m, 3H), 7.63 (d, J=8.48 Hz, 2H), 8.79 (s, 1H), 8.98 (s, 1H).
    • Example 17 N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 1-fluoro-3-isocyanatobenzene in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 3.20-4.10 (m, 8H), 4.56 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.38-7.47 (m, 4H), 7.52 (m, 1H), 7.64 (d, J=8.81 Hz, 2H), 8.64 (dd, J=7.46, 2.03 Hz, 1H), 9.00 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 529 (M+H)+.
    • Example 18 N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl)phenyl}-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for 1-fluoro-3-isocyanatobenzene in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 3.15-4.05 (m, 8H), 4.56 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.44 (m, 4H), 7.64 (d, J=8.81 Hz, 2H), 7.66 (m, 1H), 8.05 (dd, J=6.44, 2.71 Hz, 1H), 9.18 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 529 (M+H)+.
    • Example 19 N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • A solution of Example 15F (80mg, 0.22 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea (108mg, 0.268 mmol) in toluene (2 mL) and ethanol (1.5 mL) was treated with a solution of Na2CO3 (58mg) in water (1mL), degassed with nitrogen for 2 minutes, treated with Pd(PPh3)4 (13mg, 0.011 mmol), and degassed with nitrogen for another 2 minutes. The vial was capped and heated to 140-150°C for 8-10 minutes with stirring in a Smith Synthesizer microwave oven (at 300W). The reaction was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC using the conditions in Example 15H to provide 55mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.10-4.08 (m, 8H), 4.55 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.38-7.47 (m, 3H), 7.53 (t, J=7.80 Hz, 1H), 7.58-7.69 (m, 3H), 8.06 (s, 1H), 9.17 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 511 (M+H)+.
    • Example 20 N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea Example 20A 4-iodo-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-3-amine
  • The desired product was prepared by substituting 1-methylpiperazine for morpholine in Examples 15E-F. MS (ESI(+)) m/e 372 (M+H)+.
    • Example 20B N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.97 (s, 2H), 6.85 (d, J=7.12 Hz, 1H), 7.03 (m, 1H), 7.25-7.33 (m, 3H), 7.40 (d, J=8.48 Hz, 2H), 7.62 (d, J=8.48 Hz, 2H), 7.74 (m, 1H), 9.14 (s, 1H), 9.17 (s, 1H); MS (ESI(+)) m/e 490 (M+H)+.
    • Example 21 N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 6.84 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.63 Hz, 1H), 7.23-7.29 (m, 2H), 7.32 (s, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.61 (d, J=8.81 Hz, 2H), 8.76 (s, 1H), 8.94 (s, 1H); MS (ESI(+)) m/e 470 (M+H)+.
    • Example 22 N-4-{3-amino-7-[(4-methyl-1-piperarinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (s, 2H), 6.75-6.86(m, 2H), 7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.40 (d, J=8.81 Hz, 2H), 7.52 (m, 1H), 7.62 (d, J=8.48 Hz, 2H), 9.09 (s, 1H), 9.15 (s, 1H); MS (ESI(+)) m/e 474 (M+H)+.
    • Example 23 N-(4-{3-ammo-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 20A for Example 15F in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.97 (s, 2H), 6.85 (d, J=7.46 Hz, 1H), 7.28 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.41 (d, J=8.81 Hz, 2H), 7.58-7.66 (m, 3H), 8.06 (s, 1H), 8.06 (s, 1H), 9.18 (s, 1H), 9.32 (s, 1H); MS (ESI(+)) m/e 524 (M+H)+.
    • Example 24 N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-[2-fluoro-5-(trifluoromethyl)phenyl]-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (d, J=2.37 Hz, 2H), 6.84 (d, J=7.12 Hz, 1H), 7.28 (d, J=7.12 Hz, 1H), 7.38-7.45 (m, 3H), 7.52 (m, 1H), 7.62 (d, J=8.48 Hz, 2H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.99 (d, J=2.71 Hz, 1H), 9.38 (s, 1H); MS (ESI(+)) m/e 542 (M+H)+.
    • Example 25 N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 20A and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.96 (s, 2H), 6.78-6.86 (m, 2H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.27 (d, J=7.46 Hz, 1H), 7.40 (d, J=8.81 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 7.99 (dd, J=7.97, 1.86 Hz, 1H), 8.56 (d, J=2.71 Hz, 1H), 9.25 (s, 1H); MS (ESI(+)) m/e 488 (M+H)+.
    • Example 26 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea Example 26A 2,3-difluoro-6-iodobenzonitrile
  • The desired product was prepared by substituting 1,2-difluoro-4-iodobenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
    • Example 26B 4-(4-aminophenyl)-7-fluoro-1H-indazol-3-arnine
  • The desired product was prepared by substituting Example 26A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 243 (M+H)+.
    • Example 26C N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J=7.80, 4.07 Hz, 1H), 7.13 (dd, J=11.19, 7.80 Hz, 1H), 7.16 (m, 1H), 7.25 (t, J=7.97 Hz, 1H), 7.34 (m, 1H), 7.38 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 7.88 (t, J=2.03 Hz, 1H), 8.91 (s, 1H), 8.94 (s, 1H); MS (ESI(+)) m/e 440, 442 (M+H)+.
    • Example 27 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 6.74 (dd, J=7.80, 4.07 Hz, 1H), 7.03 (td, J=4.41, 2.37 Hz, 1H), 7.13 (dd, J=11.19, 7.80 Hz, 1H), 7.27 - 7.35 (m, 2H), 7.38 (d, J=8.48 Hz, 2H), 7.59 J=8.48 Hz, 2H), 7.74 (m, 1H), 8.92 (s, 1H), 8.96 (s, 1H); MS (ESI(+)) m/e 396 (M+H)+.
    • Example 28 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 6.75 (dd, J=7.80, 4.07 Hz, 1H), 7.14 (dd, J=11.19, 7.80 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (m, 3H), 8.04 (s, 1H), 8.98 (s, 1H), 9.14 (s, 1H); MS (ESI(-)) m/e 615 (M-H)-.
    • Example 29 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 6.75 (dd, J=7.80, 4.41 Hz,1H), 6.80 (d, J=7.46 Hz, 1H), 7.15 (m, 2H), 7.25 (m, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.66 (s, 1H), 8.82 (s, 1H); MS (ESI(+)) m/e 376 (M+H)+.
    • Example 30 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 3-isocyanatobenzonitrile for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J=7.80, 4.41 Hz, 1H), 7.12 (dd, J=11.19, 7.80 Hz, 1H), 7.39 (d, J=8.81 Hz, 2H), 7.43 (dt, J=7.71, 1.40 Hz, 1H), 7.51 (t, J=7.97 Hz, 1H), 7.60 (d, J=8.48 Hz, 2H), 7.70 (ddd, J=8.22, 2.29, 1.36 Hz, 1H), 8.00 (t, J=1.70 Hz, 1H), 9.00 (s, 1H), 9.09 (s, 1H); MS (ESI(+)) m/e 387 (M+H)+.
    • Example 31 N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 31A 7-[(dimethylamino)methyl]-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting N,N-dimethylamine for morpholine in Examples 15E-F. MS (ESI(+)) m/e 317 (M+H)+.
    • Example 31B N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 31A and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.82 (s, 6H), 4.51 (s, 2H), 6.82 (m, 1H), 6.91 (d, J=7.12 Hz, 1H), 7.12 (dd, J=11.53, 8.48 Hz, 1H), 7.43 (d, J=8.81 Hz, 2H), 7.43 (d, J=6.78 Hz, 1H), 7.62 (d, J=6.44 Hz, 2H), 7.99 (dd, J=7.80, 2.03 Hz, 1H), 8.56 (d, J=2.71 Hz, 1H), 9.26 (s, 1H); MS (ESI(+)) m/e 433 (M+H)+; Anal. calcd. for C24H25FN6O·2.3CF3CO2H: C, 49.44; H, 3.96; H, 12.10. Found: C, 49.51; H, 3.78; N, 12.31.
    • Example 32 N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 31A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.82 (s, 6H), 4.50 (s, 2H), 6.91 (d, J=7.12 Hz, 1H), 7.03 (m, 1H), 7.28-7.36 (m, 2H), 7.40-7.45 (m, 3H), 7.63 (d, J=8.82 Hz, 2H), 7.74 (m, 1H), 9.07 (s, 1H), 9.09 (s, 1H); MS (ESI(+)) m/e 435 (M+H)+; Anal calcd. for C23H23ClN6O·2.2CF3CO2H: C, 47.99; H, 3.70; N, 12.25. Found: C, 48.01; H, 3.41; N, 12.52.
    • Example 33 N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 31A for Example 15F in Example 19. 1H NMR (300 MHz, DMSO-d6) δ 2.82 (s, 6H), 4.50 (s, 2H), 6.91 (d, J=7.46 Hz, 1H), 7.33 (d, J=7.46 Hz, 1H), 7.43 (d, J=8.48 Hz, 2H), 7.43 (d, J=7.46 Hz, 1H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (d, J=8.82 Hz, 1H), 7.65 (d, J=8.48 Hz, 2H), 8.06 (s, 1H), 9.13 (s, 1H), 9.26 (s, 1H); MS (ESI(+)) m/e 469 (M+H)+.
    • Example 34 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea Example 34A 4-iodo-1-methyl-1H-indazol-3-amine
  • The desired product was prepared by substituting N-methylhydrazine for hydrazine hydrate in Example I A. MS (ESI(+)) m/e 274 (M+H)+.
    • Example 34B 4-(4-aminophenyl)-1-methyl-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 34A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example 1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 239 (M+H)+.
    • Example 34C N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting 1-isocyanato-3-methylbenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. The resulting product was purifed by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide the desired product. MS (ESI(+)) m/e 372 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.79 (s, 3H), 4.39 (s, 2H), 6.79 (dd, J=6.10, 1.70 Hz, 2H), 7.17 (t, J=7.80 Hz, 1H), 7.24-7.40 (m, 6H), 7.59 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.80 (s, 1H).
    • Example 35 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared as the trifluoroacetate salt by substituting isocyanatobenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 372 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 6.80 (dd, J=6.55, 0.94 Hz, 1H), 6.98 (t, J=7.49 Hz, 1H), 7.39 (d, J=8.42 Hz, 2H), 7.28-7.36 (m, 4H), 7.47 (d, J=7.49 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.70 (s, 1H), 8.80 (s, 1H).
    • Example 36 N-[4-(3-amino-1-methyl-1H-imdazol-4-yl)phenyl]-N'-(2-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-2-methylbenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 372 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.79 (s, 3H), 4.38 (s, 2H), 6.80 (d, J=6.55 Hz, 1H), 6.96 (t, J=7.96 Hz, 1H), 7.16 (t, J=7.18 Hz, 1H), 7.19 (d, J=7.49 Hz, 1H), 7.30-7.36 (m, 2H), 7.39 (d, J=8.42 Hz, 2H), 7.60 (d, J=6.55 Hz, 2H), 7.84 (d, J=7.18 Hz, 1H), 7.97 (s, 1H), 9.15 (s, 1H).
    • Example 37 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(4-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-4-methylbenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 372 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.79 (s, 3H), 6.80 (dd, J=6.55, 1.25 Hz, 1H), 7.10 (d, J=8.11 Hz, 2H), 7.30-7.39(m, 6H), 7.58 (d, J=8.42 Hz, 2H), 8.59 (s, 1H), 8.76 (s, 1H).
    • Example 38 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methoxybenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 388 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.74 (s, 3H), 3.80 (s, 3H), 6.57 (dd, J=8.11, 2.50 Hz, 1H), 6.82 (dd, J=6.71, 1.09 Hz, 1H), 6.96 (dd, J=7.96, 1.09 Hz, 1H), 7.19 (t, J=8.11 Hz, 1H), 7.21 (t, J=2.18 Hz, 1H), 7.32-7.40 (m, 4H), 7.59 (d, J=8.42 Hz, 2H), 8.73 (s, 1H), 8.81 (s, 1H).
    • Example 39 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 34B for Example 15G in Example 15H. MS (ESI(+)) m/e 376 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.37 (s, 2H), 6.77-6.81 (m, 1H), 6.80 (dd, J=6.55, 1.25 Hz, 1H), 7.14 (dd, J=8.11, 1.25 Hz, 1H), 7.29-7.36 (m, 3H), 7.40 (d, J=8.42 Hz, 2H), 7.51 (dt, J=11.85, 2.18 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 8.87 (s, 1H), 8.94 (s, 1H).
    • Example 40 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-chloro-3-isocyanatobenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 376 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.22-4.56 (br s, 2H), 6.80 (dd, J=6.55, 1.25 Hz, 1H), 7.03 (dt, J=6.63, 2.14 Hz, 1H), 7.28-7.36 (m, 4H), 7.40 (d, J=8.42 Hz, 2H), 7.60 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 8.89 (s, 1H), 8.93 (s, 1H).
    • Example 41 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-bromo-3-isocyanatobenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 384, 386 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.40 (s, 2H), 6.80 (dd, J=6.71, 1.09 Hz, 1H), 7.16 (d, J=8.11 Hz, 1H), 7.25 (t, J=7.96 Hz, 1H), 7.30-7.36 (m, 3H), 7.39 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.89 (s, 1H), 8.91 (s, 1H).
    • Example 42 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-(trifluoromethyl)benzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 426 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.80 (s, 3H), 6.81 (dd, J=6.71, 1.09 Hz, 1H), 7.31-7.37 (m, 3H), 7.40 (d, J=8.42 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.60 (d, J=9.05 Hz, 1H), 7.61 (d, J=8.73 Hz, 2H), 8.03 (s, 1H), 8.94 (s, 1H), 9.10 (s, 1H).
    • Example 43 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-2-isocyanato-4-methylbenzene and Example 34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H. MS (ESI(+)) m/e 390 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.80 (s, 3H), 6.81 (d, J=5.93 Hz, 2H), 7.11 (dd, J=11.39, 8.27 Hz, 1H), 7.31-7.37 (m, 2H), 7.40 (d, J=8.73 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.00 (dd, J=7.64, 1.72 Hz, 1H), 8.52 (d, J=2.50 Hz, 1H), 9.20 (s, 1H).
    • Example 44 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-methylphenyl)urea Example 44A N-(4-bromo-2-fluorophenyl)-N'-(3-methylphenyl)urea
  • A 0 °C solution of 4-bromo-2-fluoroaniline (1g, 5.26 mmol) in dichloromethane (10 mL) was treated dropwise with 1-isocyanato-3-methylbenzene (0.71 mL, 5.26 mmol), warmed to room temperature, stirred for 18 hours, and filtered. The filter cake was washed with dichloromethane and dried to provide 0.62g of the desired product. MS (ESI(-)) m/e 321 (M-H)-.
    • Example 44B N-[4-(3 -amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-methylphenyl)urea
  • A mixture of Example 44A (100mg, 0.31 mmol), bis(pinacolato)diboron (86mg, 0.33 mmol), Pd(dppf)Cl2 (10mg) and potassium acetate (270mg) in DMF (3 mL) was heated to 80 °C for 2 hours, treated with Example 1A (64mg, 0.24 mmol), Pd(dppf)Cl2 (6mg), Na2CO3 (78mg), and water (1mL), heated to 80°C for 18 hours, cooled to room temperature, and concentrated. The concentrate was purified by preparative HPLC using the conditions described in Example 15H to provide 27mg of the desired product as the trifuoroacetate salt. MS (ESI(+)) m/e 376 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (d, J=7.12 Hz, 3H), 6.82 (d, J=6.78 Hz, 1H), 6.86 (t, J=3.90 Hz, 1H), 7.18 (t, J=7.63 Hz, 1H), 7.26 (d, J=8.48 Hz, 2H), 7.31-7.34 (m, 3H), 7.37 (dd, J=12.21, 1.70 Hz, 1H), 8.30 (t, J=8.65 Hz, 1H), 8.66 (d, J=2.37 Hz, 1H), 9.05 (s, 1H).
    • Example 45 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 44 A-B. MS (ESI(+)) m/e 380 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 6.82 (td, J=8.42, 1.87 Hz, 1H), 6.86 (t, J=3.90 Hz, 1H), 7.12 (dd, J=8.11, 1.25 Hz, 1H), 7.28 (dd, J=8.27, 1.72 Hz, 1H), 7.32 (m, 3H), 7.38 (dd, J=12.01, 2.03 Hz, 1H), 7.53 (dt, J=11.85, 2.18 Hz, 1H), 8.26 (t, J=8.42 Hz, 1H), 8.72 (d, J=2.18 Hz, 1H), 9.33 (s, 1H).
    • Example 46 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3,5-dimethylbenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 390 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.25 (s, 6H), 6.65 (s, 1H), 6.85 (t, J=3.90 Hz, 1H), 7.10 (br s, 2H), 7.26 (d, J=8.42 Hz, 1H), 7.30 (d, J=4.06 Hz, 2H), 7.36 (dd, J=12.32, 1.72 Hz, 1H), 8.29 (t, J=8.42 Hz, 1H), 8.63 (d, J=2.50 Hz, 1H), 8.96 (s, 1H).
    • Example 47 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-ethylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-ethylbenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 390 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J=7.49 Hz, 3H), 2.59 (q, J=7.80 Hz, 2H), 6.85-6.87 (m, 2H), 7.21 (t, J=7.80 Hz, 1H), 7.28 (m, J=4.06 Hz, 2H), 7.31 (br s, 1H), 7.32 (br s, 1H), 7.34 (br s, 1H), 7.37 (dd, J=12.17, 1.87 Hz, 1H), 8.30 (t, J=8.42 Hz, 1H), 8.64 (d, J=2.18 Hz, 1H), 9.06 (s, 1H).
    • Example 48 N-[4-(3 -amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chloro-4-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 2-chloro-1-fluoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 414 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 6.83 (dd, J=4.68, 3.12 Hz, 1H), 7.24-7.40 (m, 6H), 7.84 (dd, J=6.55, 2.50 Hz, 1H), 8.23 (t, J=8.58 Hz, 1H), 8.71 (s, 1H), 9.28 (s, 1H).
    • Example 49 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluoro-4-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 2-fluoro-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 394 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.18 (s, 3H), 6.85 (m, 1H), 7.03 (dd, J=8.11, 1.87 Hz, 1H), 7.19 (t, J=8.58 Hz, 1H), 7.27 (dd, J=8.27, 1.72 Hz, 1H), 7.30 (br s, 1H), 7.31 (s, 1H), 7.37 (dd, J=12.17, 2.18 Hz, 1H), 7.46 (dd, J=12.48, 2.18 Hz, 1H), 8.26 (t, J=8.58 Hz, 1H), 8.67 (d, J=2.18 Hz, 1H), 9.20 (s, 1H).
    • Example 50 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(-)) m/e 394 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 6.85 (t, J=3.84 Hz, 1H), 7.05 (d, J=7.80, 1H), 7.26-7.35 (m, 5H), 7.38 (dd, J=12.17,1.87 Hz, 1H), 7.75 (t, J=2.03 Hz, 1H), 8.25 (t, J=8.42 Hz, 1H), 8.72 (d, J=2.18 Hz, 1H), 9.30 (s, 1H).
    • Example 51 N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting 3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile in Examples 1A-C. MS (ESI(-)) m/e 434, 436 (M-H)-; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.46 (s, 2H), 6.73 (d, J=7.46 Hz, 1H), 6.80 (d, J=6.78 Hz, 1H), 7.17 (t, J=7.63 Hz, 1H), 7.24-7.32 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.50 (d, J=7.80 Hz, 1H), 7.60 (d, J=8.14 Hz, 2H), 8.64 (s, 1H), 8.82 (s, 1H), 12.08 (s, 1H).
    • Example 52 N-{4-[3-amino-1-(2-hydroxyethyl)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting 2-hydrazinoethanol for hydrazine hydrate in Examples 1A-C. MS (ESI(+)) m/e 402 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.74 (t, J=5.76 Hz, 2H), 4.20 (t, J=5.59 Hz, 2H), 6.79 (d, J=6.78 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 7.17 (t, J=7.63 Hz, 1H), 7.23-7.40 (m, 6H), 7.59 (d, J=8.81 Hz, 2H), 8.65 (s, 1H), 8.80 (s, 1H).
    • Example 53 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-phenylacetamide Example 53A methyl 14-(3-anfino-1H-indazol-4-yl)phenyl]acetate
  • The desired product was prepared by substituting methyl (4-bromophenyl)acetate and K3PO4 for Example 44A and Na2CO3, respectively, in Example 44B. Additionally the reaction was carried our under anhydrous conditions. MS (ESI(+)) m/e 304 (M+H)+.
    • Example 53B [4-(3-amino-1H-indazol-4-yl)phenyl]acetic acid
  • A solution of Example 53A (140mg) in 1:1 methanol/10% NaOH (1 mL) was stirred at room temperature for 2 hours and adjusted to pH 3 with 10% HCl. The resulting precipitate was collected by filtration to provide 108mg of the desired product. MS (ESI(+)) m/e 268 (M+H)+.
    • Example 53C 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-phenylacetamide
  • A mixture of Example 53B (40mg, 015mmol), diisopropylethylamine (0.078 mL, 0.45 mmol), TBTU (57mg, 0.18 mmol), and aniline in THF (1 mL) was stirred for 18 hours at room temperature and concentrated. The residue was purified by preparative HPLC using the conditions described in Example 15H to provide 15mg of the desired product as the trifluoroacetate salt. MS (ESI(+)) m/e 343 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.74 (s, 2H), 6.84 (dd, J=5.09, 3.05 Hz, 1H), 7.02-7.07 (m, 1H), 7.28-7.33 (m, 4H), 7.43-7.50 (m, 4H), 7.62 (d, J=7.80 Hz, 2H).
    • Example 54 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-chlorophenyl)acetamide
  • The desired product was prepared as the trifluoroacetate salt by substituting 3-chloroaniline for aniline in Example 53C. MS (ESI(+)) m/e 377 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.75 (s, 1H), 6.84 (dd, J=5.30, 2.50 Hz, 1H), 7.11 (dd, J=7.96, 2.03 Hz, 1H), 7.31-7.36 (m, 3H), 7.44-7.49 (m, 6H), 7.85 (d, J=1.87 Hz, 1H), 10.39 (s, 1H).
    • Example 55 2-(4-(3-amino-1H-indazol-4-yl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide
  • The desired product was prepared as the trifluoroacetate salt by substituting 4-fluoro-3-methylaniline for aniline in Example 53C. MS (ESI(+)) m/e 375 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.20 (d, J=1.56 Hz, 3H), 3.71 (s, 2H), 6.84 (dd, J=5.46, 2.34 Hz, 1H), 7.07 (t, J=9.20 Hz, 1H), 7.31 (s, 1H), 7.32 (d, J=3.43 Hz, 1H), 7.40-7.60 (m, 3H), 7.45 (d, J=4.99 Hz, 2H), 7.54 (dd, J=7.02, 2.34 Hz, 1H), 10.16 (s, 1H).
    • Example 56 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetamide
  • The desired product was prepared by substituting 3-(trifluoromethyl)aniline for aniline in Example 53C, then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 411. (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.77 (s, 2H), 4.29 (s, 2H), 6.79 (dd, J=4.41, 3.39 Hz, 1H), 7.27 (s, 1H), 7.28 (d, J=1.36 Hz, 1H), 7.40-7.49 (m, 3H), 7.46 (d, J=3.39 Hz, 2H), 7.56 (t, J=7.63 Hz, 1H), 7.81 (d, J=9.83 Hz, 1H), 8.14 (s, 1H), 10.57 (s, 1H), 11.74 (s, 1H).
    • Example 57 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide
  • The desired product was prepared as the trifluoroacetate salt by substituting 3-methylaniline for aniline in Example 53C. MS (ESI(+)) m/e 357 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.72 (s, 2H), 6.83 (dd, J=4.75, 3.05 Hz, 1H), 6.86 (d, J=7.46 Hz, 1H), 7.18 (t, J=7.80 Hz, 1H), 7.30 (s, 1H), 7.32 (d, J=2.03 Hz, 1H), 7.39-7.49 (m, 6H), 10.13 (s, 1H).
    • Example 58 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-methyl)phenyl)ura Example 58A 2-fluoro-6-iodo-3-methoxybenzonitrile
  • The desired product was prepared by substituting 2-fluoro-4-iodo-1-methoxybenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
    • Example 58B 4-(4-aminophenyl)-7-methoxy-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 58A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 290 (M+H)+.
    • Example 58C N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 58B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 388 (M+M)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.92 (s, 3H), 4.30 (s, 2H), 6.69 (d, J=7.80 Hz, 1H), 6.78 (d, J=7.79 Hz, 1H), 6.80 (d, J=7.46 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.55 (d, J=8.82 Hz, 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.86 (s, 1H).
    • Example 59 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 58B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(-)) m/e 458 (M-H)-; 1H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.30 (s, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.79 (d, J=7.80 Hz, 1H), 7.38 (d, J=8.48 Hz, 2H), 7.41 (m, 1H), 7.50 (d, J=10.85 Hz, 1H), 7.58 (d, J=8.82 Hz, 2H), 8.65 (dd, J=7.46, 2.03 Hz, 1H), 8.95 (d, J=2.71 Hz, 1H), 9.29 (s, 1H), 11.88 (s, 1H).
    • Example 60 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 374 (M+H)+;1H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.75 (d, J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H), 7.29 (t, J=7.95 Hz, 2H), 7.36 (d, J=8.74 Hz, 2H), 7.47 (d, J=7.49 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 8.71 (s, 1H), 8.79 (s, 1H).
    • Example 61 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 452 and 454 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.73 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.16 (d, J=8.73 Hz, 1H), 7.25 (t, J=8.11 Hz, 1H), 7.33 (d, J=9.36 Hz, 1H), 7.36 (d, J=8.73 Hz, 2H), 7.56 (d, J=8.74 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.87 (s, 1H), 8.92 (s, 1H).
    • Example 62 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-isocyanato-3-ethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 402 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J=7.64 Hz, 3H), 2.58 (q, J=7.70 Hz, 2H), 3.94 (s, 3H), 6.73 (d, J=7.49 Hz, 1H), 6.82 (t, J=7.80 Hz, 2H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=7.80 Hz, 1H), 7.34 (s, 1H), 7.35 (d, J=8.42 Hz, 2H), 7.56 (d, J=8.42 Hz, 2H), 8.64 (s, 1H), 8.75 (s, 1H).
    • Example 63 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 2-fluoro-4-isocyanato-1-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 406 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.17 (s, 3H), 3.94 (s, 3H), 6.75 (d, J=7.49 Hz, 1H), 6.83 (d, J=7.80 Hz, 1H), 7.05 (dd, J=8.27, 2.03 Hz, 1H), 7.17 (t, J=8.58 Hz, 1H), 7.36 (d, J=8.73 Hz, 2H), 7.45 (dd, J=12.48, 1.87 Hz, 1H), 7.56 (d, J=8.73 Hz, 2H), 8.82 (s, 1H), 8.83 (s, 1H).
    • Example 64 N-(4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 460 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.95 (s, 3H), 6.79 (d, J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.38 (d, J=8.42 Hz, 2H), 7.44 (t, J=9.67 Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 7.67 (dt, J=8.66, 3.78 Hz, 1H), 8.03 (dd, J=6.40, 2.65 Hz, 1H), 9.01 (s, 1H), 9.17 (s, 1H).
    • Example 65 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-chloropbenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 408 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.76 (d, J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 7.02 (dt, J=6.63, 2.14 Hz, 1H), 7.31 (m, 2H), 7.37 (d, J=8.74 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 7.74 (m, 1H), 8.90 (s, 1H), 8.96 (s, 1H).
    • Example 66 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 442 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.76 (d, J=7.80 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.38 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 7.57-7.61 (m, 1H), 8.04 (s, 1H), 8.96 (s, 1H), 9.14 (s, 1H).
    • Example 67 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 58B for Example 15G in Example 15H. MS(ESI(+)) m/e 392 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.77 (d, J=7.80 Hz, 1H), 6.77-6.81 (m, 1H), 6.85 (d, J=7.80 Hz, 1H), 7.14 (dd, J=8.11, 0.94 Hz, 1H), 7.29-7.34 (m, 1H), 7.37 (d, J=8.73 Hz, 2H), 7.51 (dt, J=11.93, 2.30 Hz, 1H), 7.57 (d, J=8.73 Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).
    • Example 68 N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea Example 68A 2-fluoro-3-hydroxy-6-iodobenzonitrile
  • A -78 °C solution of 2-fluoro-6-iodo-3-methoxybenzonitrile (148mg, 0.53 mmol) in dichloromethane (5 mL) was treated dropwise with BBr3 (2.5 mL, 1M in dichloromethane, 2.5 mmol), warmed to room temperature, stirred for 18 hours, poured into water, and extracted with diethyl ether. The extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide 110mg of the desired product. MS (ESI(-)) m/e 262 (M-H)-.
    • Example 68B 2-fluoro-6-iodo-3-(2-methoxyethoxy)benzonitrile
  • A mixture of Example 68A (104mg, 0.39 mmol), 1-bromo-2-methoxyethane (0.088 mL) and K2CO3 (163mg) in acetone (3 mL) was heated to 60°C for 18 hours, cooled to room temperature, and partitioned between diethyl ether and water. The extract was dried (MgSO4), filtered, and concentrated to provide 122mg of the desired product MS (ESI(+)) m/e 334 (M+H)+.
    • Example 68C 4-(4-aminophenyl)-7-(2-methoxyethoxy)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 68B for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 299 (M+H)+.
    • Example 68D N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 68C and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15, then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 432 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.35 (s, 3H), 3.76 (dd, J=5.09, 3.73 Hz, 2H), 4.27 (t, J=3.05 Hz, 2H), 4.29 (s, 2H), 6.67 (d, J=7.46 Hz, 1H), 6.79 (d, J=7.80 Hz, 2H), 7.16 (t, J=7.63 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.55 (d, J=8.48 Hz, 2H), 8.63 (s, 1H), 8.76 (s, 1H), 11.83 (s, 1H).
    • Example 69 N-{4-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-phenylurea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 418 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.76 (t, J=4.41 Hz, 2H), 4.30 (t, J=4.75 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.29 Hz, 1H), 7.29 (t, J=7.46 Hz, 2H), 7.36 (d, J=8.82 Hz, 2H), 7.47 (d, J=7.46 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.72 (s, 1H), 8.80 (s, 1H).
    • Example 70 N-{4-[3-amino-7-(2-methoxyemoxy)-1H-indazol-4-yl]phenyl}-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 68C for Example 15G in Example 15H. MS (ESI(+)) m/e 436 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.28-4.30 (m, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.79 (td, J=8.58, 2.18 Hz, 1H), 6.85 (d, J=7.80 Hz, 1H), 7.14 (dd, J=8.27, 1.09 Hz, 1H), 7.31 (m, 1H), 7.37 (d, J=8.74 Hz, 2H), 7.51 (dt, J=11.93, 2.30 Hz, 1H), 7.57 (d, J=8.42 Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).
    • Example 71. N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-bromophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 496 and 498 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.28-4.30 (m, 2H), 6.73 (d, J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.33 (dd, J=8.27, 1.09 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.87 (s, 1H), 8.92 (s, 1H).
    • Example 72 N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N`-(3-chlorophenyl)urea
  • The desired product was prepared by as the trifluoroacetate salt substituting Example 68C and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 452 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.76 (t, J=4.68 Hz, 2H), 4.29 (t, J=4.68 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.85 (d, J=7.80 Hz, 1H), 7.02 (dt, J=.86, 2.03 Hz, 1H), 7.30 (m, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 8.89 (s, 1H), 8.95 (s, 1H).
    • Example 73 N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 486 (M+H)+;1H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.29-4.31 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.32 (d, J=8.11 Hz, 1H), 7.38 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 7.58-7.61 (m, 1H), 8.04 (s, 1H), 8.95 (s, 1H), 9.12 (s, 1H).
    • Example 74 N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (BSI(+)) m/e 504 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.76 (t, J=4.68 Hz, 2H), 4.29 (t, J=4.68 Hz, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.85 (d, J=7.80 Hz, 1H), 7.39 (d, J=8.74 Hz, 2H), 7.39-7.41 (m, 1H), 7.51 (m, 1H), 7.58 (d, J=8.42 Hz, 2H), 8.64 (dd, J=7.18, 2.18 Hz, 1H), 8.93 (d, J=2.81 Hz, 1H), 9.28 (s, 1H).
    • Example 75 N-(4-{3-amino-7-(2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl} phenyl)-N'-(3-methylphenyl)urea Example 75A 2-fluoro-6-iodo-3-[2-(4-morpholinyl)ethoxy]benzonitrile
  • A mixture of Example 68A (250mg, 0.95 mmol), 2-(4-morpholinyl)ethanol (0.19 mL) and triphenylphosphine on resin (630mg, 3mmol/g, 1.9 mmol) in THF (5 mL) was treated with DEAD (0.179 mL) and stirred at room temperature for about 18 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified twice by flash column chromatography on silica gel, first eluting with 5% methanol/dichloromethane then with 50% ethyl acetate/hexanes to provide 180mg of the desired product. MS (ESI(+)) m/e 377 (M+H)+.
    • Example 75B 4-(4-aminophenyl)-7-[2-(4-morpholinyl)ethoxyl-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 75A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H)+.
    • Example 75C N=(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl)phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 75B and 1-isocyanate-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 487 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.52-2.55 (m, 4H), 2.79 (t, J=5.76 Hz, 2H), 3.57-3.60 (m, 4H), 4.26 (t, J=5.76 Hz, 2H), 4.30 (s, 2H), 6.68 (d, J=7.46 Hz, 1H), 6.80 (d, J=7.80 Hz, 2H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.55 (d, J=8.82 Hz, 2H), 8.64 (s, 1H), 8.77 (s, 1H), 11.81 (s, 1H).
    • Example 76 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenylurea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 473 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.66 (m, 2H), 3.33-4.45 (br m, 8H), 4.54 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H), 7.29 (t, J=7.80 Hz, 2H), 7.36 (d, J=8.73 Hz, 2H), 7.48 (d, J=7.49 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.86 (s, 1H), 8.95 (s, 1H).
    • Example 77 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B for Example 15G in Example 15H. MS (ESI(+)) m/e 491 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.66 (t, J=4.37 Hz, 2H), 3.71 (br m, 8H), 4.53 (t, J=4.99 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.79 (td, J=8.42,1.87 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (dd, J=8.27, 1.09 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J=8.74 Hz, 2H), 7.52 (dt, J=12.09, 2.22 Hz, 1H), 7.58 (d, J=8.74 Hz, 2H), 8.97 (s, 1H), 9.06 (s, 1H).
    • Example 78 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(3-bromophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 551 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.66 (t, J=4.36 Hz, 2H), 3.30-4.32 (br m, 8H), 4.54 (t, J=4.68 Hz, 2H), 6.75 (d, J=7.49 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.16 (d, J=8.73 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.34-7.35 (m, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 7.89 (t, 3=1.87 Hz, 1H), 9.07 (s, 1H), 9.11 (s, 1H).
    • Example 79 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-(3-ethylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-ethyl-3-isocyanatabenzene for Example 15G and 1-fluoro-3 - isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 501 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J=7.49 Hz, 3H), 2.58 (q, J=7.49 Hz, 2H), 3.66 (m, 2H), 3.31-4.01 (br m, 8H), 4.53 (m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.83 (d, J=7.49 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=8.42 Hz, 1H), 7.35 (m, J=8.42 Hz, 3H), 7.58 (d, J=8.73 Hz, 2H), 8.70 (s, 1H), 8.82 (s, 1H).
    • Example 80 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(-)) m/e 557 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 3.66 (t, J=4.68 Hz, 2H), 3.32-4.20 (br m, 8H), 4.54 (t, J=4.68 Hz, 2H), 6.76 (d, J=7.49 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.39 (d, J=8.73 Hz, 2H), 7.41 (m, J=4.06 Hz, 1H), 7.51 (t, J=8.73 Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 8.64 (dd, J=7.33, 2.03 Hz, 1H), 8.97 (d, J=2.81 Hz, 1H), 9.34 (s, 1H).
    • Example 81 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxyl]-1H-indazol-4-yl}-phenyl)-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(-)) m/e 557 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 3.66 (m, 2H), 3.83 (m, 8H), 4.53 (m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.45 (t, J=9.67 Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 7.66 (dt, J=8.74, 3.74 Hz, 1H), 8.04 (dd, J=6.40, 2.65 Hz, 1H), 9.08 (s, 1H), 9.25 (s, 1H).
    • Example 82 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 507 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.31-4.00 (br m, 8H), 3.65 (m, 2H), 4.53 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d, 3=7.80 Hz, 1H), 7.01 (td, J=4.45, 2.03 Hz, 1H), 7.30 (d, J=4.99 Hz, 2H), 7.35 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 9.10 (s, 1H), 9.15 (s, 1H).
    • Example 83 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(-)) m/e 539 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 3.66 (m, 2H), 3.32-4:11 (m, 8H), 4.54 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.31 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (s, 1H), 7.61 (d, J=8.42 Hz, 2H), 7.62 (m, 1H), 8.06 (s, 1H), 9.18 (s, 1H), 9.36 (s, 1H).
    • Example 84 (2E)-3-{3-amino-4-[4-({[3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}-N,N-dimethylacrylamide Example 84A 7-bromo-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting 4-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile in Example 1A.
    • Example 84B 7-bromo-4-(4-nitrophenyl)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 84A and 4-nitrophenylboronic acid for Example 1A and Example 1B, respectively, in Example 1C. MS (ESI(+)) m/e 333, 335 (M+H)+.
    • Example 84C (2E)-3-[3-amino-4-(4-nitophenyl)-1H-indazol-7-yl]-N,N-dimethylacrylamide
  • A mixture of Example 84B (165mg), N,N-dimethylacrylamide (0.102 mL), triethylamine (0.207 mL), and Pd(o-tol3P)2Cl2 (30mg) in THF (2 mL) in a sealed tube was heated in a Smith Synthesizer microwave oven (at 300W) to 150 °C and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide 163mg of the desired product. MS (ESI(+)) m/e 352 (M+H)+.
    • Example 84D (2E)-3-[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]-N,N-dimethylacrylamide
  • A solution of Example 84C (113mg, 0.32 mmol) in a mixture of ethanol (1 mL), methanol (1 mL), and THF (1 mL) was treated with iron powder (144mg) and NH4Cl (17mg), heated to 85 °C for 4 hours, cooled to room temperature, and filtered. The filtrate was partitioned between water and ethyl acetate and the organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 75mg of the desired product. MS (ESI(+)) m/e 322 (M+H)+.
    • Example 84E (2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}-N,N-dimethylacrylamide
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 84D and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 455 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.97 (s, 3H), 3.21 (s, 3H), 6.80 (d, J=8.14 Hz, 1H), 6.86 (d, J=7.46 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 2H), 7.32 (s, 1M, 7.41 (d, J=8.82 Hz, 2H), 7.61 (d, J=8.81 Hz, 2H), 7.70 (d, J=7.80 Hz, 1H), 7.85 (d, J=15.60 Hz, 1H), 8.65 (s, 1H), 8.83 (s, 1H).
    • Example 85 (2E)-3-{3-amino-4-(4-({[(3-chlorophenyl)amino)carbonyl}amino)phenyl]-1H-indazol-7-yl}-N,N-dimethylacrylamide
  • The desired product was prepared by substituting Example 84D and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 475 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 3.21 (s, 3H), 4.44 (s, 2H), 6.86 (d, J=7.46 Hz, 1H), 7.01-7.06 (m, 1H), 7.23 (d, J=15.60 Hz, 1H), 7.30-7.32 (m, 2H), 7.43 (d, J=8.48 Hz, 2H), 7.61 (d, J=8.82 Hz, 2H), 7.70 (d, J=7.46 Hz, 1H), 7.74 (m, 1H), 7.85 (d, J=15.60 Hz, 1H), 8.96 (s, 1H), 8.98 (s, 1H), 12.17 (s, 1H).
    • Example 86 (2E)-3-(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonylamino]phenyl}-1H-indazol-7-yl)-N,N-dimethylacrylamide
  • The desired product was prepared by substituting Example 84D and 1-isocyanato-3-(trifluromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. MS (ESI(-)) m/e 507 (M-H)-; 1H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 3.21 (s, 3H), 4.44 (s, 2H), 6.86 (d, J=7.12 Hz, 1H), 7.23 (d, J=15.60 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.43 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H), 7.59 (s, 1H), 7.63 (d, J=8.81 Hz, 2H), 7.70 (d, J=7.80 Hz, 1H), 7.85 (d, J=15.26 Hz, 1H), 8.04 (s, 1H), 8.99 (s, 1H), 9.13 (s, 1H), 12.17 (s, 1H).
    • Example 87 N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenylurea Example 87A 4-(4-aminophenyl)-7-[2-(dimethylamino)ethoxyl-1H-indazol-3-amine
  • The desired product was prepared by substituting 2-(dimethylamino)ethanol for 2-(4-morpholinyl)ethanol in Example 75A-B. MS (ESI(+)) m/e 312 (M+H)+.
    • Example 87B N-(4-{3-amino-7-[2-(dimethylamino)ethoxyl-1H-indazol-4-yl}phenyl)-N'-phenylurea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 431 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 6H), 3.61 (br s, 2H), 4.49 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H), 6.98 (t, J=7.32 Hz, 1H), 7.29 (t, J=7.93 Hz, 2H), 7.36 (d, J=8.54 Hz, 2H), 7.48 (d, J=7.93 Hz, 2H), 7.59 (d, J=8.54 Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).
    • Example 88 N-(4-{3-amino-7-[2-dimethylamino)ethoxy)-1H-indazol-4-yl} phenyl)-N'-(3-bromophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 509 and 511 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 6H), 3.61 (s, 2H), 4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H), 7.16 (d, J=8.85 Hz, 1H), 7.25 (t, J=8.09 Hz, 1H), 7.35 (m, J=10.68 Hz, 1H), 7.37 (d, J=8.54 Hz, 2H), 7.60 (d, J=8.54 Hz, 2H), 7.90 (t, J=1.83 Hz, 1H), 9.17 (s, 1H), 9.21 (s, 1H).
    • Example 89 N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 445 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.95 (s, 6H), 3.61 (br s, 2H), 4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.80 (d, J=7.32 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H), 7.16 (t, J=7.78 Hz, 1H), 7.26 (d, J=8.54 Hz, 1H), 7.33 (s, 1H), 7.36 (d, J=8.54 Hz, 2H), 7.59 (d, J=8.54 Hz, 2H), 8.81 (s, 1H), 8.97 (s, 1H).
    • Example 90 N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(-)) m/e 463 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 6H), 3.61 (br s, 2H), 4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.93 Hz, 1H), 7.02 (td, J=4.42, 2.14 Hz, 1H), 7.31 (m, 2H), 7.37 (d, J=8.85 Hz, 2H), 7.60 (d, J=8.54 Hz, 2H), 7.75 (s, 1H), 9.14 (s, 1H), 9.20 (s, 1H).
    • Example 91 N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea Example 91 A 1-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)-2-pyrrolidinone
  • The desired product was prepared by substituting 1-(2-hydroxyethyl)-2-pyrrolidinone for 2-(4-morpholinyl)ethanol in Example 75A-B. MS (ESI(+)) m/e 352 (M+H)+.
    • Example 91B N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 91A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 485 (M+H)1; 1H NMR (300 MHz, DMSO-d6) δ 1.93 (m, 2H), 2.24 (t, J=8.14 Hz, 2H), 2.29 (s, 3H), 3.55 (m, 2H), 3.62 (m, 2H), 4.27 (t, J=5.43 Hz, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.35 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.78 (s, 1H).
    • Example 92 2-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide
  • The desired product was prepared by substituting Example 34A and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-m-tolyl-acetamide for Example 1A and Example 1B, respectively, in Example 53 C. The crude product was purified by preparative HPLC using the conditions described in Example 3 to provide the desired product as the trifluoroacetate salt. MS (ESI(+)) m/e 371 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.72 (s, 2H), 3.80 (s, 3H), 6.82 (dd, J=6.61, 1.19 Hz, 1H), 6.86 (d, J=7.46 Hz, 1H), 7.18 (t, J=7.80 Hz, 1H), 7.31-7.48 (m, 8H), 10.13 (s, 1H).
    • Example 93 N-[4-(3-amino-1H-indazol-4-yl)-2-methylphenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting 4-bromo-2-methylaniline for 4-bromo-2-fluoroaniline in Example 44A-B. MS (ESI(-)) m/e 370 (M-H)-; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.33 (s, 3H), 6.80 (d, J=7.46 Hz, 1H), 6.85 (dd, J=6.10, 1.70 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.34 (m, 6H), 8.03 (m, 2H), 9.03 (s, 1H).
    • Example 94 N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 91A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 505 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.93 (m, 2H), 2.24 (t, J=8.14 Hz, 2H), 3.55 (m, 2H), 3.62 (t, J=5.43 Hz, 2H), 4.27 (t, J=5.59 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.87 (d, J=8.14 Hz, 1H), 7.03 (dt, J=6.53, 2.33 Hz, 1H), 7.30 (s, 1H), 7.31 (d, J=3.73 Hz, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 7.74 (d, J=1.70 Hz, 1H), 8.89 (s, 1H), 8.95 (s, 1H).
    • Example 95 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea Example 95A 4-bromo-1,2-benzisoxazol-3-amine
  • A suspension of acetylhydroxamic acid (2.46g, 32.8 mmol) and potassium tert-butoxide (3.68g, 32.8 mmol) in DMF (40 mL) was stirred at room temperature for 30 minutes, treated with 2-bromo-6-fluorobenzonitrile (4.36g, 21.8 mmol), stirred for three hours, poured into water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5 to 20% ethyl acetate/hexanes to provide 2.5g of the desired product. MS (ESI(+)) m/e 212.9,214.9 (M+H)+.
    • Example 95B N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 95A for Example 1A in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 5.22 (s, 2H), 6.81 (d, J=7.12 Hz, 1H), 7.10-7.70 (m, 10H), 8.66 (s, 1H), 8.85 (s,1H); MS (ESI(+)) m/e 359 (M+H)+.
    • Example 96 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]urea Example 96A N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanato-2-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Example 1B.
    • Example 96B N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 95A and Example 96A for Example 1A and Example 1B, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 5.22 (s, 2H), 7.00-7.75 (m, 10H), 7.95 (d, J=7.80 Hz, 1H), 8.16 (s, 1H), 9.57 (s, 1H); MS (ESI(+)) m/e 413 (M+H)+.
    • Example 97 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 95A and Example 5A for Example 1A and Example 1B, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 5.22 (s, 2H), 6.75-6.85 (m, 1H), 7.06-7.18 (m, 2H), 7.40-7.66 (m, 6H), 8.00 (dd, J=7.97, 1.86 Hz, 1H), 8.55 (d, J=2.37 Hz, 1H), 9.25 (s, 1H); MS (ESI(+)) m/e 377 (M+H)+.
    • Example 98 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea Example 98A N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Example 1B.
    • Example 98B N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 95A and Example 98A for Example 1A and Example 1B, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 5.22 (s, 2H), 7.14 (d, J=6.78 Hz, 1H), 7.33 (d, J=7.12 Hz, 1H), 7.40-7.75 (m, 8H), 8.04 (s, 1H), 9.00 (s, 1H), 9.12 (s, 1H); MS (ESI(+)) m/e 413 (M+H)+.
    • Example 99 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea Example 99A N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
  • The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Example 1B.
    • Example 99B N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 95A and Example 99A for Example 1A and Example 1B, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-d6) δ 5.22 (s, 2H), 7.15 (d, J=7.12 Hz, 1H), 7.40-7.70 (m, 8H), 8.64 (d, J=7.46 Hz, 1H), 8.98 (s, 1H), 9.38 (s, 1H); MS (ESI(+)) m/e 431 (M+H)+.
    • Example 100 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-ffuoro-5-(trifluoromethyl)phenyl]urea Example 100A 2-fluoro-6-iodo-3-methoxybenzonitrile
  • The desired product was prepared by substituting 2-fluoro-4-iodo-1-methoxybenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
    • Example 100B 4-iodo-7-methoxy-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 1 00A for 2-bromo-6-fluorobenzonitrile in Example 95A.
    • Example 100C 4-(4-aminophenyl)-7-methoxy-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 100B for Example 15F in Example 15G. 1H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d, J=8.48 Hz, 2H), 6.94 (d, J=8.14 Hz, 1H), 7.10 (m, 3H); MS (ESI(+)) m/e 256.0 (M+H)+.
    • Example 100D N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 100C and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 3.97 (s, 3H), 5.21 (s, 2H), 7.05 (d, J=8.14 Hz, 1H), 7.17 (d, J=8.14 Hz, 1H), 7.41 (d, J=8.82 Hz, 3H), 7.45-7.56 (m, 1H), 7.61 (d, J=8.48 Hz, 2H), 8.64 (dd, J=7.12, 2.37 Hz, 1H), 8.96 (d, J=2.71 Hz, 1H), 9.34 (s, 1H); MS (ESI(+)) m/e 461 (M+H)+.
    • Example 101 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.96 (s, 3H), 5.21 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.04 (d, J=8.14 Hz, 1H), 7.10-7.35 (m, 4H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.82 Hz, 2H), 8.64 (s, 1H), 8.81 (s, 1H); MS (ESI(+)) m/e 389(M+H)+.
    • Example 102 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 100C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 3.96 (s, 3H), 5.21 (s, 2H), 7.05 (d, J=7.80 Hz, 1H), 7.17 (d, J=8.14 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (m, 3H), 8.04 (s, 1H), 8.96 (s, 1H), 9.10 (s, 1H); MS (ESI(+)) m/e 443.0 (M+H)+.
    • Example 103 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 3.96 (s, 3H), 5.20 (s, 2H), 7.00-7.06 (m, 2H), 7.16 (d, J=8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.39 (d, J=8.81 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 7.73 (t, J=2.03 Hz, 1H), 8.92 (s, 1H), 8.94 (s, 1H); MS (ESI(+)) m/e 409 (M+H)+.
    • Example 104 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.96 (s, 3H), 5.21 (s, 2H), 6.75-6.90 (m, 1H), 7.00-7.20 (m, 3H), 7.39 (d, J=8.81 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.00 (dd, J=7.63, 1.86 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.22 (s, 1H); MS (ESI(+)) m/e 407.0 (M+H)+.
    • Example 105 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-fluoro-5-trifluoromethyl)phenyl]urea Example 105A 4-iodo-7-(4-morpholinylmethyl)-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 15E for 2-bromo-6-fluorobenzonitrile in Example 95A.
    • Example 105B 4-(4-aminophenyl)-7-(4-morpholinylmethyl)-1,2-benzisoxazol-3-amine
  • The desired product was prepared by subsituting Example 105A for Example 15F in Example 15G. 1H NMR (300 MHz, DMSO-d6) δ 2.38-2.45 (m, 4H), 3.55-3.63 (m, 4H), 3.70 (s, 2H), 5.21 (s, 2H), 5.38 (s, 2H), 6.69 (d, J=8.48 Hz, 2H), 7.02 (d, J=7.46 Hz, 1H), 7.15 (d, J=8.48 Hz, 2H), 7.45 (d, J=7.46 Hz, 1H).
    • Example 105C N-{4-(3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl)phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 105B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 7.13 (d, J=7.46 Hz, 1H), 7.35-7.55 (m, 5H), 7.64 (d, J=8.81 Hz, 2H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.99 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 530(M+H)+.
    • Example 106 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 105B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, CF3CO2D) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 7.12 (d, J=7.46 Hz, 1H), 7.33 (d, J=7.46 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H), 7.50-7.68 (m, 5H), 8.04 (s, 1H), 9.04 (s, 1H), 9.16 (s,1H); MS (ESI(+)) m/e 512 (M+H)+.
    • Example 107 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 105B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.22 (s, 2H), 6.95-7.06 (m, 1H), 7.12 (d, J=7.46 Hz, 1H), 7.25-7.38 (m, 2H), 7.44 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.80 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 7.70-7.78 (m, 1H), 8.99 (s, 2H); MS (ESI(+)) m/e 478 (M+H)+.
    • Example 108 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 105B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.23 (s, 2H), 6.80 (d, J=7.80 Hz, 1H), 7.05-7.35 (m, 5H), 7.42 (d, J=8.48 Hz, 1H), 7.52 (d, J=7.12 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS (ESI(+)) m/e 458 (M+H)+.
    • Example 109 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 105B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.35-2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 6.75-6.85 (m, J=2.37 Hz, 1H), 7.05-7.18 (m, 2H), 7.44 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.80 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 8.00 (dd, J=7.80, 1.70 Hz, 1H), 8.55 (d, J=2.37 Hz, 1H), 9.25 (s, 1H); MS (ESI(+)) m/e 476 (M+H)+.
    • Example 110 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared by substituting Example 105B and 1-isocyanato-3,5-dimethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 6H), 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.23 (s, 2H), 6.63 (s, 1H), 7.05-7.15 (m, 3H), 7.42 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.46 Hz, 1H), 7.61 (d, J=8.81 Hz, 2H), 8.59 (s, 1H), 8.84 (s, 1H); MS (ESI(+)) m/e 472 (M+H)+.
    • Example 111 N-{4-[3-amino-7-(4-morpholinylmetllyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-phenoxyphenyl)urea
  • The desired product was prepared by substituting Example 105B and 1-isocyanato-3-phenoxybenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.40-2.48 (m, 4H), 3.55-3.64 (m, 4H), 3.73 (s, 2H), 5.21 (s, 2H), 6.60-6.68 (m, 1H), 7.00-7.20 (m, 5H), 7.25-7.32 (m, 2H), 7.35-7.45 (m, 4H), 7.51 (d, J=7.46 Hz, 1H), 7.59 (d, J=8.82 Hz, 2H), 8.84 (s, 1H), 8.87 (s, 1H); MS (ESI(+)) m/e 536.1 (M+H)+.
    • Example 112 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 105B and 1-bromo-3 - isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.40-2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.73 (s, 2H), 5.22 (s, 2H), 7.10-7.35 (m, 4H), 7.43 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.46 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 7.88 (t, J=1.86 Hz, 1H), 8.96 (s, 2H); MS (ESI(+)) m/e 524 (M+H)+.
    • Example 113 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}-phenyl)-N'-[3 - (trifluoromethyl)phenyl]urea Example 113A 4-iodo-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 75A for 2-bromo-6-fluorobenzonitrile in Example 95A.
    • Example 113B 4-(4-aminophenyl)-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 113A for Example 15F in Example 15G. 1H NMR (300 MHz, DMSO-d6) δ 2.45-2.60 (m, 4H), 2.76 (t, J=5.59 Hz, 2H), 3.50-3.70 (m, 4H), 4.28 (t, J=5.59 Hz, 2H), 5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d, J=8.48 Hz, 2H), 6.92 (d, J=7.80 Hz, 1H), 7.05-7.18 (m, 3H); MS (ESI(+)) m/e 355.0 (M+H)+.
    • Example 113C N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 113B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.45-2.60 (m, 4H), 2.78 (t, J=5.59 Hz, 2H), 3.50-3.65 (m, 4H), 4.31 (t, J=5.59 Hz, 2H), 5.21 (s, 2H), 7.03 (d, J=8.14 Hz, 1H), 7.19 (d, J=8.14 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.81 Hz, 2H), 7.53(t, J=7.80 Hz, 1H), 7.57-7.66 (m, 3H), 8.04 (s, 1H), 8.96 (s, 1H), 9.10 (s, 1H); MS (ESI(+)) m/e 542.1, 540.1.
    • Example 114 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxyl-1,2-benzisoxazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 113B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.45-2.55 (m, 4H), 2.78 (t, J=5.59 Hz, 2H), 3.50-3.65 (m, 4H), 4.31 (t, J=5.76 Hz, 2H), 5.21 (s, 2H), 6.75-6.84 (m, 1H), 7.03 (d, J=8.14 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.19 (d, J=8.14 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.00 (dd, J=7.80, 2.03 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.22 (s, 1H); MS (ESI(+)) m/e 506.1 (M+H)+.
    • Example 115 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 113B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.45-2.55 (m, 4H), 2.78 (t, J=5.26 Hz, 2H), 3.50-3.67 (m, 4H), 4.31 (t, J=5.09 Hz, 2H), 5.21 (s, 2H), 7.03 (d, J=7.80 Hz, 1H), 7.19 (d, J=7.80 Hz, 1H), 7.35-7.70 (m, 6H), 8.64 (dd, J=6.78,1.36 Hz, 1H), 8.96 (d, J=2.37 Hz, 1H), 9.34 (s, 1H); MS (ESI(+)) m/e 560.1 (M+H)+.
    • Example 116 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 113B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.45-2.55(m, 4H), 2.78 (t, J=5.26 Hz, 2H), 3.50-3.70 (m, 4H), 4.31 (t, J=4.92 Hz, 2H), 5.21 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.02 (d, J=7.80 Hz, 1H), 7.10-7.30 (m, 4H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.66 (s, 1H), 8.83 (s, 1H); MS (ESI(+)) m/e 488 (M+H)+.
    • Example 117 N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 68C and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. MS (ESI(+)) m/e 450 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.36 (s, 3H), 3.76 (t, J=4.75 Hz, 2H), 4.26-4.29, (m, 2H), 4.29 (s, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz, 1H),6.82 (m, 1H), 7.11 (dd, J=11.53, 8.14 Hz, 1H), 7.36 (d, J=8.82 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 2.03 Hz, 1H), 8.52 (d, J=2.37 Hz, 1H), 9.16 (s, 1H).
    • Example 118 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and I-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 505 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.73 (m, 2H), 3.71 (m, 6H), 4.04 (m, 2H), 4.53 (m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.81 (m, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.82 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.01 (s, 1H), 8.52 (d, J=2.71 Hz, 1H), 9.18 (s, 1H).
    • Example 119 N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea Example 119A 2-fluoro-6-iodo-3-(methoxymethoxy)benzonitrile
  • A 0 °C solution of Example 68A (250mg, 0.95 mmol) in THF (5 mL) at room temperature was treated with NaH (25mg, 95%, 1.05 mmol), stirred for 5 minutes, treated with chloromethyl methyl ether (0.108 mL, 1.4 mmol), stirred overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide 0.21g of the desired product. Rf=0.4 (10% ethyl acetate/hexanes).
    • Example 119B N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 119A and 1-fluoro-2-isocyanato-4-methylbenzene for 2-fluoro-6-iodobenzonitrile and 1-isocyanato-3-methylbenzene, respectively, in Examples 1A-1C. MS (ESI(+)) m/e 436 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.46 (s, 3H), 4.33 (s, 2H), 5.34 (s, 2H), 6.69 (d, J=7.80 Hz, 1H), 6.78-6.83 (m, 1H), 6.92 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 1.70 Hz, 1H), 8.52 (d, J=2.71 Hz, 1H), 9.17 (s, 1H), 11.90 (s, 1H).
    • Example 120 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • A mixture of Example 119B (90mg) and a 1:1:1 mixture of 3N HCl/methanol/THF (3 mL) was heated to 50°C for 3 hours, concentrated to half its original volume, and partitioned between saturated NaHCO3 and ethyl acetate. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromcthane to provide 30mg of the desired product. MS (ESI(+)) m/e 392 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.25 (s, 2H), 6.60 (d, J=5.76 Hz, 2H), 6.82 (m, J=5.09, 3.05 Hz, 1H), 7.11 (m, 2H), 7.33 (d, J=8.48 Hz, 1H), 7.54 (d, J=8.81 Hz, 2H), 8.01 (dd, J=7.97, 2.20 Hz, 1H), 8.51 (d, J=2.71 Hz, 1H), 9.14 (s, 1H), 9.84 (s, 1H), 11.58 (s, 1H).
    • Example 121 N-[4-(3-amino-7-hydroxyr-1H-indazol-4-yl)phenyl)-N'-(3-fluorophenyl)urea Example 121A 4-(4-aminophenyl)-7-(methoxymethoxy)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 119A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 285 (M+H)+.
    • Example 121B N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-fluprophenyl)urea
  • The desired product was prepared by substituting Example 121A for Example 15G in Example 15H.
    • Example 121C N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 121B for Example 119B in Example 120, then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(+)) m/e 378 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 6.68-6.72 (m, 2H), 6.79 (td, J=8.34, 2.34 Hz, 1H), 7.14 (d, J=8.11 Hz, 1H), 7.31 (m, 1H), 7.35 (d, J=8.42 Hz, 2H), 7.51 (dt, J=12.01, 2.26 Hz, 1H), 7.56 (d, J=8.42 Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).
    • Example 122 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea Example 122A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 121A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 122B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 122A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(+)) m/e 438 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 6.69-6.73 (m, 2H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.32-7.34 (m, 1H), 7.35 (d, J=8.42 Hz, 2H), 7.56 (d, J=8.73 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.90 (s, 1H), 8.95 (s, 1H).
    • Example 123 N-[4-(3-amino)-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea Example 123A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-ethylphenyl)urea
  • The desired product was prepared by substituting Example 121A and 1-ethyl-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 123B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 123A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(+)) m/e 388 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J=7.49 Hz, 3H), 2.58 (q, J=7.49 Hz, 2H), 6.65-6.70 (m, 2H), 6.83 (d, J=7.49 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=8.11 Hz, 1H), 7.33-7.34 (m, 3H), 7.55 (d, J=8.42 Hz, 2H), 8.64 (s, 1H), 8.74 (s, 1H).
    • Example 124 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea Example 124A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 121A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 124B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 124A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(+)) m/e 446 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 6.68-6.72 (m, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.38-7.40 (m, 1H), 7.51 (m, 1H), 7.57 (d, J=8.73 Hz, 2H), 8.64 (dd, J=7.17, 2.18 Hz, 1H), 8.93 (d, J=2.81 Hz, 1H), 9.28 (s, 1H).
    • Example 125 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)pheny]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea Example 125A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 121A and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 125B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 125A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(-)) m/e 444 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 6.72-6.76 (m, 2H), 7.36 (d, J=8.42 Hz, 2H), 7.44 (t, J=9.67 Hz, 1H), 7.58 (d, J=8.73 Hz, 2H), 7.65-7.68 (m, 1H), 8.03 (dd, J=6.39, 2.65 Hz, 1H), 9.02 (s, 1H), 9.19 (s, 1H).
    • Example 126 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea Example 126A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 121A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 126B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 126A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(-)) m/e 392 (M-H)-; 1H NMR (500 MHz, DMSO-d6) δ 6.69-6.73 (m, 1H), 7.01-7.03 (m, 1H), 7.30-7.31 (m, 2H), 7.35 (d, J=8.73 Hz, 2H), 7.56 (d, J=8.73 Hz, 2H), 7.74 (d, J=1.87 Hz, 1H), 8.91 (s, 1H), 8.98 (s, 1H).
    • Example 127 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea Example 127A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 121A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 127B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 127A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H. MS (ESI(+)) m/e 428 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 6.70-6.74 (m, 2H), 7.32 (d, J=7.49 Hz, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H), 7.58 (d, J=8.42 Hz, 2H), 7.60 (d, J=9.04 Hz, 1H), 8.04 (s, 1H), 8.96 (s, 1H), 9.14 (s, 1H).
    • Example 128 N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-phenylurea Example 128A N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-phenylurea
  • The desired product was prepared by substituting Example 121A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
    • Example 128B N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-phenylurea
  • The desired product can be prepared by substituting Example 128A for Example 119B in Example 120. MS (ESI(-)) m/e 358 (M-H)-; 1H NMR (300 MHz, DMSO-d6) δ 6.57-6.64 (m, 2H), 6.97 (t, J=7.29 Hz, 1H), 7.29 (t, J=8.13 Hz, 2H), 7.32 (d, J=8.82 Hz, 2H), 7.47 (d, J=7.46 Hz, 2H), 7.54 (d, J=8.82 Hz, 2H), 8.71 (s, 1H), 8.77 (s, 1H).
    • Example 129 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenylurea Example 129A 4-(4-aminophenyl)-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-3-amine
  • The desired product was prepared by substituting 2-(1-pyrrolidinyl)ethanol for 2-(4-morpholinyl)ethanol in Examples 75A and 75B. MS (ESI(+)) m/e 338 (M+H)+.
    • Example 129B N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenylurea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 457 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.08 (br s, 2H), 3.25 (br s, 4H), 3.68 (br s, 2H), 4.46 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H), 7.29 (t, J=7.80 Hz, 2H), 7.36 (d, J=8.73 Hz, 2H), 7.47 (d, J=7.49 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 8.74 (s, 1H), 8.82 (s, 1H).
    • Example 130 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A for Example 15G in Example 15H. MS (ESI(+)) m/e 475 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.92 (br s, 2H), 2.07 (br s, 2H), 3.24 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.49 Hz, 1H), 6.79 (td, J=8.50, 2.34 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (dd, J=8.11, 1.25 Hz, 1H), 7.29-7.34 (m, 1H), 7.37 (d, J=8.73 Hz, 2H), 7.52 (dt, J=12.01, 2.26 Hz, 1H), 7.58 (d, J=8.73 Hz, 2H), 9.00 (s, 1H), 9.08 (s, 1H).
    • Example 131 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3 - isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 489 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.07 (br s, 2H), 2.28 (s, 3H), 3.25 (br s, 2H), 3.69 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.80-6.82 (m, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.38, 8.26 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.73 Hz, 21-1), 7.99 (dd, J=7.80, 1.56 Hz, 1H), 8.53 (d, J=2.49 Hz, 1H), 9.20 (s, 1H).
    • Example 132 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 129A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 471 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.07 (br s, 2H), 2.29 (s, 3H), 3.25 (br s, 2H), 3.69 (br s, 4H), 4.48 (t, J=4.80 Hz, 2H), 6.77 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.49 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.11 Hz, 1H), 7.33 (s, 1H), 7.36 (d, J=8.73 Hz, 2H), 7.59 (d, J=8.73 Hz, 2H), 8.79 (s, 1H), 8.95 (s, 1H).
    • Example 133 N-(4-{3-amino-7-[2-(1-Pyrrolidinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-(3-bromophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 535 and 537 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (d, J=8.11 Hz, 1H), 7.25 (t, J=8.11 Hz, 1H), 7.34 (d, J=9.36 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 7.89 (t, J=1.87 Hz, 1H), 9.06 (s, 1H), 9.10 (s, 1H).
    • Example 134 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 543 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.08 (br s, 2H), 3.25 (br s, 2H), 3.69 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.39 (d, J=8.42 Hz, 2H), 7.41 (m, 1H), 7.51 (t, J=9.67 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 8.64 (dd, J=7.33, 2.34 Hz, 1H), 8.94 (d, J=2.49 Hz, 1H), 9.30 (s, 1H).
    • Example 135 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 491 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.76 (d, J=7.49 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H), 7.02 (m, 1H), 7.31 (d, J=5.30 Hz, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.73 Hz, 2H), 7.74 (s, 1H), 9.10 (s, 1H), 9.15 (s, 1H).
    • Example 136 N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxyl-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 525 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.93 (br s, 2H), 2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.80 Hz, 1H), 7.60 (d, J=8.42 Hz, 2H), 7.60 (d, J=6.55 Hz, 1H), 8.05 (s, 1H), 9.10 (s, 1H), 9.28 (s, 1H).
    • Example 137 N-(4-{3-amino-7-[2-(diethylamino)ethoxyl-1H-indazol-4-yl}phenyl)-N'-phenylurea Example 137A 4-(4-aminophenyl)-7-[2-(diethylamino)ethoxyl-1H-indazol-3-amine
  • The desired product was prepared by substituting 2-(diethylamino)ethanol for 2-(4-morpholinyl)ethanol in Examples 75A and 75B. MS (ESI(+)) m/e 340 (M+H)+.
    • Example 137B N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenylurea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 459 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.17 Hz, 6H), 3.33 (br s, 4H), 3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.49 Hz, 1H), 7.29 (t, J=7.95 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 7.48 (d, J=7.80 Hz, 2H), 7.58 (d, J=8.73 Hz, 2H), 8.83 (s, 1H), 8.91 (s, 1H).
    • Example 138 N-(4-{3-amino-7-[2-(diethylamino)ethoxyl-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A for Example 15G in Example 15H. MS (ESI(+)) m/e 477 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.33 Hz, 6H), 3.34 (br s, 4H), 3.60 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.76 (d, J=7.80 Hz, 1H), 6.79 (t, J=8.5 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (d, J=8.11 Hz, 1H), 7.31 (q, J=7.61 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (dt, J=11.93, 2.14 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 9.02 (s, 1H), 9.11 (s, 1H).
    • Example 139 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 491 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.33 Hz, 6H), 2.28 (s, 3H), 3.33 (br d, J=8.42 Hz, 4H), 3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.80-6.82 (m, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.38, 8.26 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 7.99 (dd, J=7.95, 1.72 Hz, 1H), 8.54 (d, J=2.50 Hz, 1H), 9.22 (s, 1H).
    • Example 140 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 473 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.33 Hz, 6H), 2.29 (s, 3H), 3.34 (br s, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.49 Hz, 1H), 6.80 (d, J=7.17 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.11 Hz, 1H), 7.32 (s, 1H), 7.35 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 8.72 (s, 1H), 8.87 (s, 1H).
    • Example 141 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-bromophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 537 and 539 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.33 Hz, 6H), 3.30-3.35 (m, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.33-7.35 (m, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 7.89 (m, 1H), 9.05 (s, 1H), 9.09 (s,1H).
    • Example 142 N-(4-{3-amino-7-(2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 545 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.17 Hz, 6H), 3.33 (br s, 4H), 3.62 (br s, 2H), 4.50 (t, J=4.80 Hz, 2H), 6.77 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.39 (m, J=8.42 Hz, 3H), 7.51 (t, J=9.85 Hz 1H), 7.60 (d, J=8.73 Hz, 2H), 8.64 (dd, J=7.17, 2.18 Hz,1H), 8.97 (d, J=2.81 Hz, 1H), 9.35 (s, 1H).
    • Example 143 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 493 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.17 Hz, 6H), 3.34 (br s, 4H), 3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz,1H), 6.88 (d, J=7.80 Hz, 1H), 7.02 (td, J=4.37, 2.18 Hz, 1H), 7.30-7.31 (m, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 7.74 (s, 1H), 9.01 (s, 1H), 9.06 (s, 1H).
    • Example 144 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indaxol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 527 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.33 Hz, 6H), 3.32-3.34 (br s, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.49 Hz, 1H), 7.31 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H), 7.60-7.61 (m, 3H), 8.05 (s, 1H), 9.12 (s, 1H), 9.30 (s, 1H).
    • Example 145 N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,1-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea Example 145A 3-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)-1,5,5-trimethyl-2,4-imidazolidinedione
  • The desired product was prepared by substituting 3-(2-hydroxyethyl)-1,5,5-trimethyl-2,4-imidazolidinedione for 2-(4-morpholinyl)ethanol in Examples 75A and 75B. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.80 (s, 3H), 3.81 (t, J=6.27 Hz, 2H), 4.32 (t, J=6.27 Hz, 2H), 5.19 (s, 2H), 6.57 (d, J=7.80 Hz, 1H), 6.65 (d, J=8.14 Hz, 2H), 6.76 (d, J=7.80 Hz, 1H), 7.07 (d, J=8.14 Hz, 2H), 11.59 (s, 1H); MS (ESI(+)) m/e 409 (M+H)+.
    • Example 145B N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 145A and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.29 (s, 3H), 2.81 (s, 3H), 3.83 (t, J=5.93 Hz, 2H), 4.35 (t, J=5.93 Hz, 2H), 6.68 (d, J=7.80 Hz,1H), 6.81 (t, J=7.46 Hz, 2H), 7.05-7.45 (m, 5H), 7.56 (d, J=8.48 Hz, 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.75 (s, 1H); MS (ESI(+)) m/e 542 (M+H)+.
    • Example 146 N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 145A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.81 (s, 3H), 3.83 (t, J=6.27 Hz, 2H), 4.35 (t, J=6.44 Hz, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 6.95-7.06 (m, 1H), 7.25-7.40 (m, 4H), 7.56 (d, J=8.81 Hz, 2H), 7.73 (s, 1H), 8.86 (s, 1H), 8.93 (s, 1H), 11.74 (s, 1H); MS (ESI(+)) m/e 562 (M+H)+.
    • Example 147 N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 145A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.28 (s, 3H), 2.81 (s, 3H), 3.83 (t, J=6.27 Hz, 2H), 4.35 (t, J=6.27 Hz, 2H), 6.67 (d, J=7.80 Hz, 1H), 6.70-6.90 (m, 2H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 7.90-8.10 (dd, J=7.97,1.86 Hz, 1H), 8.52 (d, J=2.71 Hz, 1H), 9.17 (s, 1H), 11.72 (s, 1H); MS(ESI(+)) m/e 560 (M+H)+.
    • Example 148 N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 145A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.81 (s, 3H), 3.83 (t, J=6.27 Hz, 2H), 4.35 (t, J=6.44 Hz, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.82 (d, J=8.14 Hz, 1H), 7.25-7.45 (m, 3H), 7.45-7.65 (m, 4H), 8.04 (s,1H), 8.90 (s,1H), 9.09 (s, 1H), 11.73 (s, 1H); MS(ESI(+)) m/e 596(M+H)+.
    • Example 149 N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 149A N-(4-bromo-2-ethylphenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • A solution of 4-bromo-2-ethylaniline (200mg) in dichloromethane (10 mL) was treated with 1-fluoro-2-isocyanato-4-methylbenzene (151mg), stirred at room temperature overnight, diluted with hexanes, and filtered. The filter cake provided 227mg of the desired product. MS (ESI(+)) m/e 351,353 (M+H)+.
    • Example 149B N-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • A mixture of Example 149A (219mg, 0.62 mmmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (190mg, 0.75 mmol), potassium acetate (183mg), and PdCl2(dppf)CH2Cl2 (15mg) in DMF (6 mL) was degassed then heated to 80 °C for 2 hours. The mixture was used directly in the next reaction.
    • Example 149C N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 149B and PdCl2(dpp)·CH2Cl2 for Example 1B and Pd(PPh3)4, respectively, in Example 1C. Additionally, DMF was used in place of DME. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J=7.46 Hz, 3H), 2.28 (s, 3H), 2.71 (q, J=7.46 Hz, 2H), 4.35 (s, 2H), 6.75-6.85 (m, 2H), 7.12 (dd, J=11.53, 8.14 Hz, 1H), 7.25-7.35 (m, 4H), 7.99 (d, J=8.14 Hz, 1H), 8.06 (dd, J=7.80, 2.03 Hz, 1H), 8.44 (s, 1H), 8.99 (d, J=2.03 Hz, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 404(M+H)+.
    • Example 150 N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanato-3-(trifluoromethyl)benzene for 1-fluoro-2-isocyanato-4-methylbenzene in Examples 149A-C. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J=7.46 Hz, 3H), 2.71 (q, J=7.69 Hz, 2H), 4.35 (s, 2H), 6.75-6.90 (m, 1H), 7.20-7.40 (m, 4H), 7.45-7.60 (m, 3H), 7.94 (d, J=8.14 Hz, 1H), 8.07 (s, 1H), 8.13 (s, 1H), 9.43 (s, 1H), 11.72 (s,1H); MS (ESI(+)) m/e 440 (M+H)+.
    • Example 151 N-[4-(3-amino-7-fluoro-1H-indazol-4-y)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 6.74-6.83 (m, 2H), 7.13 (m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.99 (d, J=6.44 Hz, 1H), 8.52 (d, J=2.45 Hz, 1H), 9.21 (s, 1H); MS (ESI(+)) m/e 394 (M+H)+.
    • Example 152 N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea Example 152A 2,3-difluoro-4-(hydroxymethyl)-6-iodobenzonitrile
  • A -78 °C solution of Example 26A (5.0g, 18.9 mmol) in THF was treated with LDA (2M in hexanes, 11.5 mL, 22.6 mmol), stirred for 1 hour at -78 °C, treated with methyl formate (2.34 mL, 37.8 mmol), stirred at -78 °C for 30 minutes, warmed to 0 °C for I hour, quenched with saturated NH4Cl and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was immediately dissolved in ethanol (100 mL), cooled to 0 °C, and treated portionwise with NaBH4 (1.08g). The reaction was stirred at 0 °C for 2 hours, quenched with acetone, stirred for 5 minutes, poured into water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to give 1.02 g of the desired product. Rf = 0.84 (ethyl acetate).
    • Example 152B (3-amino-7-fluoro-4-iodo-1H-indazol-6-yl)methanol
  • The desired product was prepared by substituting Example 152A for 2-fluoro-6-iodobenzonitrile in Example 1A. Rf = 0.53 (ethyl acetate).
    • Example 152C N-{4-(3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • A mixture of Example 152B (50mg, 0.16 mmol), Example 5A (66mg, 0.18 mmol), Pd(PPh3)4 (9mg, 0.008 mmol), and Na2CO3 (43mg, 0.4 mmol) in toluene (2 mL), ethanol (1 mL), and water (1 mL) was degassed and heated at 140 °C for 8 minutes with stirring using a Smith Synthesizer in a septa capped 5 mL process vial at 300W. The samples were cooled using 40 psi pressurized air. The mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7µm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40mL/min to provide 26mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.65 (d, J=1.36 Hz, 2H), 6.81 (m, 1H), 6.86 (d, J=5.76 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 2.03 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.21 (s, 1H); MS (ESI(+)) m/e 424 (M+H)+.
    • Example 153 N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 98A for Example 5A in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 4.65 (d, J=1.70 Hz, 2H), 6.87 (d, J=5.76 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.97 Hz,1H), 7.58-7.64 (m, 3H), 8.04 (s, 1H), 8.99 (s, 1H), 9.14 (s, 1H); MS (ESI(+)) m/e 460 (M+H)+; Anal. calcd. for C22H17F4N5O2·1.0CF3CO2H: C, 50.27; H, 3.15; N, 12.21; Found: C, 50.15; H, 3.15; N, 12.41.
    • Example 154 N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 4.65 (d, J=1.36 Hz, 2H), 6.86 (d, J=5.76 Hz, 1H), 7.03 (td, J=4.41, 2.03 Hz, 1H), 7.27-7.36 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 7.74 (m, 1H), 8.93 (s, 1H), 8.96 (s, 1H); MS (ESI(+)) m/e 426 (M+H)+.
    • Example 155 N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 1B for Example 5A in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.65 (d, J=1.36 Hz, 2H), 6.80 (d, J=7.46 Hz, 1H), 6.84 (d, J=5.76 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25 (d, J=7.80Hz, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 406 (M+H)+.
    • Example 156 N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 4.65 (d, J=1.02 Hz, 2H), 6.80 (td, J=8.65, 2.71 Hz, 1H), 6.84 (d, J=5.76 Hz, 1H), 7.14 (d, J=9.16 Hz, 1H), 7.32 (m, 1H), 7.38 (d, J=8.48 Hz, 2H), 7.51 (dt, J=11.87, 2.20 Hz, 1H), 7.59 (d, J=8.48 Hz, 2H), 12.13 (s, 1H); MS (ESI(+)) m/e 410 (M+H)+.
    • Example 157 N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 157A 4-[(diethylamino)methyl]-2,3-difluoro-6-iodobenzonitrile
  • A 0 °C solution of Example 152A (350mg, 1.18 mmol) in dichloromethane (10 mL) was treated with triethylamine (0.25 mL, 1.78 mmol) and methanesulfonyl chloride (0.1 mL, 1.3 mmol), stirred at 0 °C for 1 hour, treated with diethylamine (0.245 mL, 2.37 mmol), and overnight at room temperature. The mixture was partitioned between 1N NaOH and dichloromethane and the organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 3:1 hexanes/ethyl acetate to provide 0.263g of the desired product. MS (ESI(+)) 351 (M+H)+.
    • Example 157B 6-[(diethylamino)methyl]-7-fluoro-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 157A for 2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) 363 (M+H)+.
    • Example 157C N-(4-{3-amino-6-[(diethylamino)methy]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 157B for Example 152B in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J=7.29 Hz, 6H), 2.28 (s, 3H), 3.18 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.82 (ddd, J=7.71, 5.17, 2.03 Hz, 1H), 6.94 (d, J=5.76 Hz, 1H), 7.12 (dd, J=11.36,8.31 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H), 7.63 (d, J=8.82 Hz, 2H), 7.99 (dd, J=7.97, 1.87 Hz, 1H), 8.56 (d, J=2.71 Hz, 1H), 9.27 (s, 1H), 9.36 (br s, 1H); MS (ESI(+) 477 (M+H)+.
    • Example 158 N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 157B and Example 98A for Example 152B and Example 5A, respectively, in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J=7.29 Hz, 6H), 3.18 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.94 (d, J=5.76 Hz, 1H), 7.33 (d, J=7.80 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.60 (m, 1H), 7.65 (d, J=8.48 Hz, 2H), 8.06 (s, 1H), 9.14 (s, 1H), 9.27 (s, 1H), 9.34 (br s, 1H); MS (ESI(+)) m/e 515 (M+H)+.
    • Example 159 N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 157B and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 152B and Example 5A, respectively, in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J=7.29 Hz, 6H), 3.19 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.94 (d, J=5.76 Hz, 1H), 7.03 (dt, J=6.44, 2.20 Hz, 1H), 7.27-7.37(m, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.63 (d, J=8.48 Hz, 2H), 7.75 (m, 1H), 9.06 (s, 1H), 9.32 (br s, 1H); MS (ESI(+)) m/e 481 (M+H)+.
    • Example 160 N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-y}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 157B and Example 1B for Example 152B and Example 5A, respectively, in Example 152C. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J=7.12 Hz, 6H), 2.29 (s, 3H), 3.18 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.81 (d, J=7.12 Hz, 1H), 6.94 (d, J=5.76 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.42 (d, J=8.48 Hz, 2H), 7.63 (d, J=8.48 Hz, 2H), 8.74 (s, 1H), 8.93 (s, 1H), 9.34 (br s, 1H); MS (ESI(+)) m/e 461 (M+H)+.
    • Example 161 N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea Example 161A 4-iodo-7-[(3-pyridinyloxy)methyl]-1H-indazol-3-amine
  • The desired product was prepared by substituting 3-pyridinol for morpholine in Examples 15E-F.
    • Example 161B N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 161A and Example 98A for Example 152B and Example 5A, respectively, in Example 152C then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. 1H NMR (500 MHz, DMSO-d6) δ 4.38 (s, 2H), 5.40 (s, 2H), 7.32 (d, J=7.17 Hz, 1H), 7.34-7.38 (m, 2H), 7.42 (d, J=8.42 Hz, 2H), 7.52 (dd, J=15.59, 7.80 Hz, 2H), 7.58-7.64 (m, 4H), 8.04 (s, 1H), 8.19 (d, J=4.68 Hz, 1H), 8.39 (d, J=2.50 Hz, 1H), 8.96 (s, 1H), 9.12 (s, 1H), 11.92 (s, 1H); MS (ESI(+)) m/e 519 (M+H)+.
    • Example 162 N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 162A 2-(4-iodo-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione
  • A mixture of Example 1A (1.09g) and phthalic anhydride (0.75g) in dioxane (15 mL) was stirred overnight at 120 °C and concentrated. The residue was triturated from diethyl ether (15 mL) to provide 0.51g of the desired product. MS (ESI(+)) m/e 388 (M+H)+.
    • Example 162B 2-{4-iodo-1-[2-(4-morpholinyl)ethyl]-1H-indazol-3-yl}-1H-isoindole-1,3(2H)-dione
  • A mixture of Example 162A (100mg), 4-(2-chloroethyl)morpholine (48mg), and Na2CO3 (82mg) in DMF (5 mL) was heated overnight at 80 °C, cooled to room temperature, and partitioned between 1N HCl and ethyl acetate. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide 45mg of the desired product. MS (ESI(+)) m/e 503 (M+H)+.
    • Example 162C 4-iodo-1-[2-(4-morpholinyl)ethyl]-1H-indazol-3-amine
  • A mixture of hydrazine hydrate (0.058 mL) and Example 162B (120mg, 0.24 mmol) in ethanol (5mL) was stirred at 0 °C for 3 hours and concentrated. The residue was purified by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide 95mg of the desired product.
    • Example 162D N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C for Example 152B in Example 152C. MS (ESI(+)) m/e 489 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.45 (d, J=4.07 Hz, 4H), 2.68 (t, J=6.61 Hz, 2H), 3.54 (t, J=4.05 Hz, 4H), 4.26 (t, J=6.44 Hz, 2H), 4.41 (s, 2H), 6.78-6.83 (d, J=6.78 Hz, 2H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.31 (t, J=8.48 Hz, 1H), 7.36-7.41 (m, 3H), 7.59 (d, J=8.48 Hz, 2H), 8.01 (d, J=7.46 Hz, 1H), 8.54 (s, 1H), 9.21 (s, 1H).
    • Example 163 N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting 162C for Example 15F in Examples 15G-H. MS (ESI(+)) m/e 475 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.58 (t, J=5.77 Hz, 2H), 3.32-3.83 (br m, 8H), 4.55 (t, J=6.24 Hz, 2H), 6.79 (td, J=8.42, 1.87 Hz, 1H), 6.88 (d, J=6.55 Hz, 1H), 7.15 (dd, J=8.26,1.09 Hz,1H), 7.29-7.34 (m, 1H), 7.38-7.42 (m, J=8.11, 8.11 Hz, 3H), 7.48 (d, J=8.11 Hz, 1H), 7.52 (dt, J=11.85,2.18 Hz, 1H), 7.62 (d, J=8.73 Hz, 2H), 9.06 (s, 1H), 9.12 (s, 1H).
    • Example 164 N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and 1-chloro-3-isocyanatobenzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H. MS (ESI(+)) m/e 491 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.58 (t, J=5.92 Hz, 2H), 3.38-3.92 (br m, 8H), 4.55 (t, J=6.39 Hz, 2H), 6.88 (d, J=6.86 Hz, 1H), 7.02-7.04 (m, 1H), 7.31-7.32 (m, 2H), 7.38-7.41 (m, J=7.95, 7.95 Hz, 3H), 7.48 (d, J=8.11 Hz, 1H), 7.62 (d, J=8.73 Hz, 2H), 7.74 (s, 1H), 9.09 (s, 1H), 9.11 (s, 1H).
    • Example 165 N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]1-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H. MS (ESI(+)) m/e 525 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.32-3.83 (br m, 8H), 3.58 (t, J=5.77 Hz, 2H), 4.55 (t, J=6.39 Hz, 2H), 6.88 (d, J-7.17 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.39-7.42 (m, 3H), 7.48 (d, J=8.42 Hz, 1H), 7.53 (t, J=7.95 Hz, 1H), 7.61 (d, J=8.73 Hz, 1H), 7.64 (d, J=8.73 Hz, 2H), 8.05 (s, 1H), 9.15 (s, 1H), 9.29 (s, 1H).
    • Example 166 N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and 1-isocyanato-3-methylbenzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H. MS (ESI(+)) m/e 471 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.58 (t, J=5.77 Hz, 2H), 3.39-3.88 (br m, 8H), 4.55 (t, J=6.39 Hz, 2H), 6.80 (d, J=7.49 Hz, 1H), 6.87 (d, J=6.86 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.42 Hz, 1H), 7.32 (s, 1H), 7.37-7.41 (m, 3H), 7.48 (d, J=8.11 Hz, 1H), 7.61 (d, J=8.42 Hz, 2H), 8.75 (s, 1H), 8.93 (s, 1H).
    • Examples 167-1 and 167-II N-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea and N-[4-(3-amino-4-bromo-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea Example 167A 2,4-dibromo-6-fluorobenzonitrile
  • The desired product was prepared by substituting 2,4-dibromo-6-fluorobenzoic acid (prepared as described in Tetrahedron Lett. 1996, 37, 6551-6554) for Example 15A in Examples 15B and 15C.
    • Example 167B 4,6-dibromo-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 167A for 2-fluoro-6-iodobenzonitrile in Example 1A. 1H NMR (DMSO-d6) δ 11.99 (1H, br s), 7.48 (1H, d, J = 1.6 Hz), 7.24 (1H, s), 5.22 (1H, d, J = 8.0 Hz).
    • Example 167-I and 167-II N-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea and N-[4-(3-amino-4-bromo-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea
  • A mixture of Example 167B (0.060g, 0.021 mmol), Example 1B (0.073g, 0.21 mmol), Na2CO3 (0.052g, 0.49 mmol), and Pd(PPh3)4 (0.014g, 0.012 mmol) in 2:1 DME/water (1.2 mL) was heated to 85 °C in a sealed tube overnight. The reaction was treated with additional Pd(PPh3)4 (0.028g, 0.024 mmol), heated for two days, treated with additional catalyst (0.028g, 0.024 mmol), heated to 160 °C for 2 hours, and cooled to room temperature. The mixture was diluted with ethyl acetate and dichloromethane, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with methanol/dichloromethane (2:100 to 5:100), then purified by preparative HPLC with 30-100% CH3CN/5 mM ammonium acetate buffer over 9 minutes to provide the desired products.
    Example 167-1: LC/MS 434.2 (M-H)-, LC retention time 3.00 min. 1H NMR (DMSO-d6) δ 7.508 (2H, d, J = 8.4 Hz), 7.454 (1H, d, J = 1.2 Hz), 7.407 (2H, d, J = 8.4 Hz), 7.325 (1H, s), 7.257 (1H d, J = 6.0 Hz), 7.166 (1H, m), 6.888 (1H, s), 6.799 (1H, d, J = 7.6 Hz), 4.397 (2H, s), 2.328 (3H, s).
    Example 167-II: LC/MS 434.0 (M-H)-, LC retention time 2.87 min.1H NMR (DMSO-d6) δ 11.88 (1H, br s), 8.961 (1H, br s), 8.782 (1H, br s), 7.637 (2H, d, J = 8.8 Hz), 7.560 (1H, d, J = 8.8 Hz), 7.414 (2H, d, J = 1.2 Hz), 7.352 (1H, d, J = 1.2 Hz), 7.319 (1H, s), 7.252 (1H, d, J = 7.6 Hz), 7.181-7.142 (1H, m), 6.796 (1H, d, J = 7.6 Hz), 5.147 (2H, d, J = 9.2 Hz), 2.285 (3H, s).
    • Example 168 N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting N-(2-chloroethyl)-N,N-dimethylamine for 4-(2-chloroethyl)morpholine in Example 162. MS (ESI(+)) m/e 447 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.87 (s, 3H), 2.88 (s, 3H), 3.54 (q, J=5.65 Hz, 2H), 4.52 (t, J=6.10 Hz, 2H), 6.79-6.84 (m, 1H), 6.88 (d, J=6.10 Hz, 1H), 7.12 (dd,J=11.36, 8.31 Hz, 1H), 7.37-7.42 (m, 3H), 7.50 (d, J=7.79 Hz, 2H), 7.61 (d, J=8.48 Hz, 2H), 7.99 (dd, J=8.14, 2.03 Hz, 1H), 8.55 (d, J=2.37 Hz, 1H), 9.24 (s, 1H).
    • Example 169 N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea Example 169A 1-[2-(dimethylamino)ethyl]-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting N-(2-chloroethyl) N,N-dimethylamine for 4-(2-chloroethyl)morpholine in Example 162A-C.
    • Example 169B N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urca
  • The desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 169A and N-{3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 152B (50mg, 0.16 mmol) and Example 5A, respectively, in Example 152C. MS (ESI(+)) m/e 449 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.87 (s, 3H) 2.88 (s, 3H) 3.55 (q, J=5.65 Hz, 2H) 4.52 (t, J=6.27 Hz, 2H) 6.87 (dd, J=6.95, 0.85 Hz, 1H) 7.01-7.05 (m, 1H) 7.30-7.32 (m, 2H) 7.38-7.42 (m, 3H) 7.50 (d, J=8.48 Hz, 1H) 7.61 (d, J=8.48 Hz, 2H) 7.73-7.75 (m, 1H) 9.01 (s, 1H) 9.04 (s, 1H).
    • Example 170 N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl} oxy)ethyl]methanesulfonamide Example 170A tert-butyl 2-(3-cyano-2-fluoro-4-iodophenoxy)ethylcarbamate
  • The desired product was prepared by substituting tert-butyl 2-hydroxyethylcarbamate for 2-(4-morpholinyl)ethanol in Example 75A. Rf = 0.8 (1:1 ethyl acetate/hexanes).
    • Example 170B N-(2-(3-cyano-2-fluoro-4-iodophenoxy)ethyl)methanesulfonamide
  • A mixture of Example 170A (317mg, 0.78 mmol) in TFA (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature for 10 minutes and concentrated. The residue was partitioned between saturated NaHCO3 and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in pyridine (5 mL), treated with methanesulfonyl chloride (0.07 mL), stirred at room temperature for 6 hours, concentrated, and partitioned between ethyl acetate and IN HCl. The organic extract was dried (Na2SO4) filtered, and concentrated to provide the desired product. MS (ESI) m/e 383 (M-H)-.
    • Example 170C N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]etlayl}methanesulfonamide
  • The desired product was prepared by substituting Example 170B for 2-fluoro-6-iodobenzonitrile in Example 1A.
    • Example 170D N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 170C for Example 152B in Example 152C. MS (APCI(+)) m/e 513 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H) 2.99 (s, 3H) 3.43 (q, J=5.76 Hz, 2H) 4.22 (t, J=5.42 Hz, 2H) 4.35 (s, 2H) 6.70 (d, J=7.46 Hz, 1H) 6.80 (d, J=7.80 Hz, 1H) 6.80-6.83 (m, 1H) 7.08-7.19 (m, 2H) 7.37 (d, J=8.81 Hz, 2H) 7.56 (d, J=8.81 Hz, 2H) 8.01 (dd, J=7.97, I.86 Hz, 1H) 8.52 (d, J=2.37 Hz, 1H) 9.17 (s, 1H) 11.77 (s, 1H).
    • Example 171 4-(1H-indol-5-yl)-1H-indazol-3-amine
  • The desired product was prepared by substituting 5-indolylboronic acid and Example 1A for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 15F, respectively, in Example 15G. 1H NMR (300 MHz, DMSO-d6) δ 4.28 (s, 2H), 6.50 (ddd, J=3.05,2.03, 0.68 Hz, 1H), 6.80 (dd, J=6.27, 1.53 Hz, 1H), 7.18 (dd, J=8.14, 1.70 Hz, 1H), 7.25 (m, 2H), 7.43 (m, 1H), 7.51 (d, J=8.14 Hz, 1H), 7.60 (m, 1H), 11.23 (s, 1H), 11.63 (s, 1H); MS (ESI(+)) m/e 249 (M+H)+.
    • Example 172 N-{4-[3-amino-1-(2-methoxyethyl)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea Examples 172A and 172B 2-[4-iodo-2-(2-methoxyethyl)-2H-indazol-3-yl]-1H-isoindole-1,3(2H)-dione and 2-[4-iodo-1-(2-methoxyethyl)-1H-indazol-3-yl]-1H-isoindole-1,3(2H)-dione
  • A mixture of Example 162A (1.2 g, 3.1 mmol), 1-bromo-2-methoxyethane (0.35 mL, 3.7 mmol) and K2CO3 (857 mg, 6.2 mmol) in DMF (15 mL) wa stirred overnight at rt, then concentrated to dryness. The residue was partitioned between EtOAc and H2O. The extract was dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with 2% MeOH/CH2Cl2. The product was obtained as a mixture of Examples 172A and 172B (∼3:1).
    • Example 172C and 172D 4-iodo-1-(2-methoxyethyl) - 1H-indazol-3-amine and 4-iodo-2-(2-methoxyethyl)-1H-indazol-3-amine
  • A mixture of the isomers 172A and 172B (970 mg, 2.2 mmol) was dissolved in EtOH (10 mL) and the solution was chilled to 0 °C and treated dropwise with hydrazine monohydrate (0.58 mL), then stirred for 3 h at rt. The mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel, eluting with 0-4% MeOH/ CH2Cl2. A mixture of isomers 172C and 172D was obtained. MS (ESI(+)) m/e 317.8 (M+H)+.
    • Example 172E and 172F 4-(4-aminophenyl)-1-(2-methoxyethyl)-1H-indazol-3-amine and 4-(4-aminophenyl) - 2-(2-methoxyethyl) - 1H-indazol-3-amine
  • A mixture of Examples 172E and 172F was prepared by substituting a mixture of Examples 172C and 172D for Example 15F in Example 15G. MS (ESI(+)) m/e 283.0 (M+H)+.
    • Example 172G N-{4-[3-amino-1-(2-methoxyethyl)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was obtained by substituting a mixture of Examples 172E and 172F for Example 15G and I-fluoro-2-isocyanato-4-methylbenzene for 1-fluoro-3-isocyanatobenzene in Example 15H. Additionally, DMF was used in place of CH2Cl2. The mixture was concentrated and the residue was purified by preparative HPLC as in example 3 to provide the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 3.21 (s, 3 H) 3.69 (t, J=5.4 Hz, 2 H) 4.32 (t, J=5.4 Hz, 2 H) 6.79-6.84 (m, 2 H) 7.12 (dd, J=11.4, 8.3 Hz, 1 H) 7.31 (dd, J=8.5, 6.8 Hz, 1 H) 7.38-7.43 (m, 3 H) 7.59 (d, J=8.5 Hz, 2 H) 8.01 (dd, J=7.8, 2.0 Hz, 1 H) 8.54 (d, J=2.4 Hz, 1 H) 9.21 (s, 1 H) MS (ESI(+)) m/c 434.0 (M+H)+.
    • Example 174 N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared by substituting Example 145A and 1-isocyanato-3,5-dimethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The product was purified by preparative HPLC as in example 3. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.27 (s, 6 H) 2.24 (s, 6 H) 2.81 (s, 3 H) 3.83 (t, J=6.4 Hz, 2 H) 4.35 (t, J=6.4 Hz, 2 H) 6.62 (s, 1 H) 6.68 (d, J=7.8 Hz, 1 H) 6.83 (d, J=7.8 Hz, 1 H) 7.09 (s, 2 H) 7.34 (d, J=8.8 Hz, 2 H) 7.55 (d, J=8.8 Hz, 2 H) 8.54 (s, 1 H) 8.74 (s, 1 H) 11.75-11.85 (br. s., 1 H) MS (ESI(+)) m/e 556.3 (M+H)+.
    • Example 175 N-[4-(3-amino-1H-indazol-4-yl)-2,6-dimethylphenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 4-bromo-2,6-dimethylaniline for 4-bromo-2-ethylaniline in Examples 149A-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3 H) 2.30 (s, 6 H) 6.77-6.80 (m, 1 H) 6.87 (dd, J=5.8, 2.4 Hz, 1 H) 7.10 (dd, J=11.5, 8.5 Hz, 1 H) 7.20 (s, 2 H) 7.33 (s, 1 H) 7.35 (d. J=3.4 Hz, 1 H) 7.98 (d, J=6.8 Hz, 1 H) 8.23 (s, 1 H) 8.54-8.65 (br. s., 1 H) 11.99-12.20 (br. s., 1 H) MS (ESI(+)) m/e 404.2 (M+H)+.
    • Example 176 N-[4-(3-amino-1H-indazol-4-yl)-2,6-dimethylphenyl]-N'-(3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanato-3-(trifluoromethyl)benzene and 4-bromo-2,6-dimethylaniline for 1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline, respectively, in Examples 149A-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.30 (s, 6 H) 6.84 (dd, J=5.3, 2.5 Hz, 1 H) 7.21 (s, 2 H) 7.27-7.32 (m, 3 H) 7.50 (t, J=8.0 Hz, I H) 7.62 (d, J=8.5 Hz, 1 H) 7.96 (s, 1 H) 8.03 (s, 1 H) 9.17 (s, 1 H) 11.88-11.99 (m, 1 H) MS (ESI(+)) m/e 440.2 (M+H)+.
    Figure imgb0011
    • Example 177 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-hydroxyphenyl)urea
  • The desired product was prepared by substituting 4-iodo-1-isocyanatobenzene and 3-hydroxyaniline for 1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline, respectively, in Examples 149A-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.38 (ddd, J=8.1, 2.3, 0.9 Hz, 1 H) 6.82 (ddd, J=8.0, 2.0, 0.9 Hz, 1 H) 6.86 (dd, J=6.4, 1.7 Hz, 1 H) 7.03-7.08 (m, 2 H) 7.29-7.35 (m, 2 H) 7.40 (d, J=8.5 Hz, 2 H) 7.59 (d, J=8.8 Hz, 2 H) 8.65 (s, 1 H) 8.80 (s, 1 H) 9.12-9.53 (br. s., 1 H) 11.80-12.39 (br. s., 1 H) MS (ESI(+)) m/e 360.2 (M+H)+.
    • Example 178 N-[2-({3-amino-4-[4-({[(3-methylphenyl)aminol]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide Example 178A N-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)methanesulfonamide
  • The desired product was prepared by substituting Example 170C and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1A and 1B, respectively, in Example 1C.
    • Example 178B N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}aminol)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide
  • The desired product was prepared by substituting Example 178A and 1-isocyanato-3-methylbenzene for Example 150 and 1-fluoxo-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 2.99 (s, 3 H) 3.44 (q, J=5.8 Hz, 2 H) 4.23 (t, J=5.4 Hz, 2 H) 6.73 (d, J=7.8 Hz, 1 H) 6.80 (d, J=7.8 Hz, 1 H) 6.84 (d, J=7.8 Hz, 1 H) 7.12-7.19 (m, 2 H) 7.25 (d, J=8.1 Hz, 1 H) 7.31 (s, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.56 (d, J=8.5 Hz, 2 H) 8.63 (s, 1 H) 8.77 (s, 1 H), 11.91-12.07 (br. s., 1 H) MS (ESI(+)) m/e 495.1 (M+H)+.
    • Example 179 N-{2-[(3-amino-4-14-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide
  • The desired product was prepared by substituting Example 178A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.99 (s, 3 H) 3.44 (q, J=6.1 Hz, 2 H) 4.22 (t, J=5.4 Hz, 2 H) 6.72 (d, J=7.8 Hz, I H) 6.82 (d, J=7.8 Hz, 1 H) 7.17 (t, J=6.1 Hz, 1 H) 7.38-7.42 (m, 3 H) 7.48-7.54 (m, 1 H) 7.58 (d, J=8.8 Hz, 2 H) 8.65 (dd, J=7.5, 2.0 Hz, 1 H) 8.94 (d, J=3.1 Hz, 1 H) 9.29 (s, 1 H) 11.87 (s, 1 H) MS (ESI(+)) m/e 567.2 (M+H)+.
    • Example 180 N-[2-({3-amino-4-[4-({[(3-chlorophenyl)aminolcarbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide
  • The desired product was prepared by substituting Example 178A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.99 (s, 3 H) 3.43 (q, J=5.8 Hz, 2 H) 4.22 (t, J=5.4 Hz, 2 H) 6.71 (d, J=7.8 Hz, 1 H) 6.81 (d, J=7.8 Hz, 1 H) 7.03 (dt, J=6.7, 2.3 Hz, 1 H) 7.15-7.19 (m, 1 H) 7.27-7.32 (m, 2 H) 7.37 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 7.73 (t, J=1.9 Hz, 1 H) 8.86 (s, 1 H) 8.93 (s, 1 H) 11.84 (s, 1 H) MS (ESI(+)) m/e 515.1 (M+H)+.
    • Example 181 N-{2-{(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H indazol-7-yl)oxy]ethyl}methanesulfonamide
  • The desired product was prepared by substituting Example 178A and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.99 (s, 3 H) 3.43 (q, J=5.8 Hz, 2 H) 4.22 (t, J=5.4 Hz, 2 H) 6.71 (d, J=7.5 Hz, 1 H) 6.81 (d, J=7.8 Hz, 1 H) 7.17 (t, J=5.8 Hz, 1 H) 7.30-7.34 (m, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.50-7.61 (m, 4 H) 8.04 (t, J=2.2 Hz, 1 H) 8.91 (s, 1 H) 9.09 (s, 1 H) 11.82 (s, 1 H) MS (ESI(-)) m/e547.1 (M-H)-.
    • Example 182 N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea Example 182A 6-bromo-1H-indazol-3-amine
  • The desired product was prepared by substituting 4-bromo-2-fluorobenzonitrile for 2-fluoro-6-iodobenzonitrile in Example 1A.. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.44 (s, 2 H) 7.02 (dd, J=8.48, 1.70 Hz, 1 H) 7.41 (d, J=1.70 Hz, 1 H) 7.63 (d, J=8.48 Hz, 1 H) 11.49 (s, 1 H).
    • Example 182C N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 182A and 1B for 1A and 5A respectively, in Example 5B. MS (ESI(+)Q1MS m/z 358 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 5.34 (s, 2 H) 6.79 (d, J=7.32 Hz, 1 H) 7.15-7.20 (m, 2 H) 7.25 (d, J=8.24 Hz, 1 H) 7.31 (s, 1 H) 7.38 (s, 1 H) 7.55 (d, J=8.85 Hz, 2 H) 7.62 (m, 2 H) 7.72 (d, J=8.54 Hz, 1 H) 8.75 (s, 1 H) 8.89 (s, 1 H) 11.38 (s, 1 H)
    • Example 183 3-amino-N-(3-methylphenyl)-6-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazole-1-carboxamide Example 183A 6-(4-aminophenyl)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 182A for Example 1A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.19 (s, 2 H) 5.27 (s, 2 H) 6.64 (d, J=8.48 Hz, 2 H) 7.10 (dd, J=8.48, 1.36 Hz, 1 H) 7.25 (s, 1 H) 7.37 (d, J=8.48 Hz, 2 H) 7.64 (d, J=8.48 Hz, 1 H) 11.25 (s, 1 H).
    • Example 183B 3-amino-N-(3-methylphenyl)-6-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H indazole-1-carboxamide
  • The desired product was prepared by substituting example 183A and 1-isocyanate-3-methylbenzene for 15G and 1-fluoro-3-isocyanatobenzene, respectively in example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 2.32 (s, 3 H) 6.37 (s, 2 H) 6.80 (d, J=7.1 Hz, 1 H) 6.91 (d, J=7.5 Hz, 1 H) 7.17 (t, J=7.8 Hz, 1 H) 7.22 (t, J=7.8 Hz, 1 H) 7.25 (d, J=8.5 Hz, 1 H) 7.33 (s, 1 H) 7.46-7.50 (m, 1 H) 7.55-7.61 (m, 4 H) 7.68 (d, J=8.8 Hz, 2 H) 7.95 (d, J=8.1 Hz, 1 H) 8.39 (d, J=0.7 Hz, 1 H) 8.62 (s, 1 H) 8.83 (s, 1 H) 9.37 (s, 1 H) MS (ESI(+)) m/e 490.0 (M+H)+.
    • Example 184 N-[3-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea Example 184A N-(3-methylphenyl)-N'-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
  • The desired product was prepared by substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example 1B. MS (ESI(+)) m/e 352.9 (M+H)+.
    • Example 184B N-[3-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 184A for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3 H) 6.78-6.83 (m, 2 H) 7.05-7.09 (m, 1 H) 7.15 (t, J=7.8 Hz, 1 H) 7.22 (d, J=8.1 Hz, 1 H) 7.28-7.31 (m, 3 H) 7.38-7.43 (m, 2 H) 7.63 (s, 1 H) 8.63 (s, 1 H) 8.81 (s, H) 11.74 (s, 1 H) MS (ESI(+)) m/e 358.1 (M+H)+.
    • Example 185 N-4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea Example 185A 4-iodo-7-methyl-1H-indazol-3-amine
  • The desired compound was prepared by substituting Example 15C for 2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 273.8 (M+H)+.
    • Example 185B 4-(4-aminophenyl)-7-methyl-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 185A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 239.0 (M+H)+.
    • Example 185C N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl
  • The desired product was prepared by substituting Example 185B and 1-isocyanate-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 2.42 (s, 3 H) 6.70 (d, J=7.1 Hz, 1 H) 6.80 (d, J=7.5 Hz, 1 H) 7.05 (dd, J=7.1, 1.0 Hz, 1 H) 7.16 (t, J=7.8 Hz, 1 H) 7.25 (d, J=8.5 Hz, 1 H) 7.32 (s, 1 H) 7.36 J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.63 (s, 1 H) 8.77 (s, 1 H) 11.75 (s, 1 H) MS (ESI(+)) m/e 371.6 (M+H)+.
    • Example 186 N-[4-3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 185B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 6.80 (d, J=7.1 Hz, 1 H) 7.00-7.06 (m, 1 H) 7.15 (dd, J=7.1, 1.0 Hz, 1 H) 7.28-7.32 (m, 2 H) 7.39 (d, J=8.8 Hz, 2 H) 7.60 (d, J=8.8 Hz, 2 H) 7.73-7.75 (m, I H) 8.98 (s, 1 H) 9.01 (s, 1 H) 12.01-12.46 (br. s., 1 H) MS (ESI(+)) m/e 382.0 (M+H)+.
    • Example 187 N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl1-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 185B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.43 (s, 3 H) 6.73 (d, J=7.1 Hz, 1 H) 7.08 (d, J=7.1 Hz, 1 H) 7.32 (d, J=8.1 Hz, 1 H) 7.39 (d, J=8.5 Hz, 2 H) 7.53 (t, J=7.8 Hz, 1 H) 7.58-7.61 (m, 3 H) 8.04 (s, 1 H) 8.94 (s, 1 H) 9.11 (s, 1 H) 11.87 (s, 1 H) MS (ESI(+)) m/e 426.0 (M+H)+.
    • Example 188 N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 185B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.43 (s, 3 H) 6.71 (d, J=7.1 Hz, 1 H) 7.06 (d, J=7.8 Hz, 1 H) 7.38-7.43 (m, 3 H) 7.48-7.55 (m, 1 H) 7.59 (d, J=8.5 Hz, 2 H) 8.65 (dd, J=7.3, 2.2 Hz, 1 H) 8.95 (d, J=2.7 Hz, 1 H) 9.30 (s, 1 H) 11.78 (s, 1 H) MS (ESI(+)) m/e 444.1 (M+H)+.
    • Example 189 N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 185B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-ffuoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 1MHz, DMSO-D6) δ ppm 2.44 (s, 3 H) 6.76 (d, J=7.1 Hz, 1 H) 7.11 (dd, J=7.3, 0.9 Hz, 1 H) 7.16 (ddd, J=7.8, 2.0, 1.0 Hz, 1 H) 7.25 (t, J=8.0 Hz, 1 H) 7.33 (ddd, J=8.1, 2.0, 1.0 Hz, 1 H) 7.39 (d, J=8.5 Hz, 2 H) 7.59 (d, J=8.8 Hz, 2 H) 7.88 (t, J=1.9 Hz, 1 H) 8.94 (s, 1 H) 8.97 (s, 1 H) 12.06 (s, 1 H) MS (ESI(+)) m/e 463.0, 438.0 (M+H)+.
    • Example 190 N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 185B for Example 15G in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 6.76-6.82 (m, 2 H) 7.13-7.17 (m, 2 H) 7.32 (td, J=8.5, 6.8 Hz, 1 H) 7.39 (d, J=8.8 Hz, 2 H) 7.52 (dt, J=12.1, 2.3 Hz, 1 H) 7.60 (d, J=8.5 Hz, 2 H) 8.96 (s, 1 H) 9.03 (s, 1 H) 12.08-12.44 (br. s., 1 H) MS (ESI(+))m/e 376.1 (M+H)+.
    • Example 191 N-4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 185B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and I-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 2.45 (s, 3 H) 6.78 (d, J=6.8 Hz, 1 H) 6.79-6.84 (m, 1 H) 7.08-7.15 (m, 2 H) 7.39 (d, J=8.5 Hz, 2 H) 7.59 (d, J=8.8 Hz, 2 H) 8.01 (dd, J=7.8, 1.7 Hz, 1 H) 8.53 (d, J=2.4 Hz, 1 H) 9.21 (s, 1 H) 12.00-12.33 (br. s., 1 H) MS (ESI(+)) m/e 390.0 (M+H)+.
    • Example 192 N-[4-(3-amino-7-methy]-1H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
  • The desired product was prepared by substituting Example 185B and 3-isocyanatobenzonitrile for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.44 (s, 3 H) 6.77 (d, J=7.1 Hz, 1 H) 7.12 (dd, J=7.1, 1.0 Hz, 1 H) 7.40 (d, J=8.5 Hz, 2 H) 7.43 (dt, J=7.8, 1.4 Hz, 1 H) 7.51 (t, J=8.0 Hz, 1 H) 7.60 (d, J=8.5 Hz, 2 H) 7.70 (ddd, J=8.3, 2.2, 1.0 Hz, 1 H) 8.01 (t, J=1.7 Hz, 1 H) 9.05 (s, I H) 9.14 (s, 1 H) 11.98-12.22 (br. s., 1 H) MS m/e (ESI(+)) 383.1 (M+H)+.
    • Example 193 N-[4-(3-amino-1H-indazol4-yl)-2-(trifluoromethoxy)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 4-bromo-2-(trifluoromethoxy)aniline for 4-bromo-2-ethylaniline in Examples 149A-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 6.82-6.91 (m, 2 H) 7.14 (dd, J=11.5, 8.1 Hz, 1 H) 7.32 (d, J=1.0 Hz, 1 H) 7.34 (s, I H) 7.47-7.52 (m, 2 H) 8.03 (dd, J=8.0, 1.9 Hz, 1 H) 8.42 (d, J=8.8 Hz, 1 H) 9.03 (s, 1 H) 9.24 (d, J=2.4 Hz, 1 H) 11.83-12.13 (br. s., 1 H) MS (ESI(+)) m/e 460.1 (M+H)+.
    • Example 194 N-[5-(3-amino-1H-indazol-4-yl)pyridin-2-yl]-N'-(2-fluoro-5-methylphenyl)urea Example 194A N-(5-bromopyridin-2-yl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 2-amino5-bromopyridine and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 324.0 (M+H)+.
    • Example 194B N-[5-(3-amino-1H-indazol-4-yl)pyridin-2-yl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 194A for Example 44A in Example 44B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.30 (s, 3 H) 6.83-6.92 (m, 2 H) 7.15 (dd, J=11.2, 8.5 Hz, 1 H) 7.34 (s, 1 H) 7.35 (s, 1 H) 7.54 (d, J=8.5 Hz, 1 H) 7.90 (dd, J=8.7, 2.5 Hz, 1 H) 8.07 (dd, J=7.5, 2.0 Hz, 1 H) 8.38 (d, J=2.4 Hz, 1 H) 9.95 (s, 1 H) 10.88 (s, 1 H) 12.02 (s, 1 H) MS (ESI(+)) m/e 377.1 (M+H)+.
    • Example 195 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea Example 195A 7-fluoro-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 26A for 2-fluoro-6-iodobenzonitrile in Example 1A.
    • Example 195B N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 195A for Example 1A and N-(2-fluoro-5-(trifluoromethyl)phenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ, ppm 6.74 (dd, J=7.8, 4.1 Hz, 1 H) 7.13 (dd, J=11.5, 7.8 Hz, 1 H) 7.37-7.43 (m, 3 H) 7.51 (dd, J=10.9, 8.5 Hz, 1 H) 7.61 (d, J=8.5 Hz, 2 H) 8.64 (dd, J=7.3, 2.2 Hz, 1 H) 8.96 (d, J=3.1 Hz, 1 H) 9.32 (s, 1 H) 12.25 (s, 1 H) MS (ESI(+)) m/e 448.0 (M+H)+.
    • Example 196 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea
  • The desired product was prepared by substituting Example 195A for Example 1A and N-(4-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.74 (dd, J=7.8, 4.1 Hz, 1 H) 7.11 (dd, J=7.8, 1.4 Hz, 1 H) 7.15 (d, J=8.5 Hz, 2 H) 7.37 (d, J=8.5 Hz, 2 H) 7.49 (dd, J=9.3, 4.9 Hz, 2 H) 7.58 (d, J=8.5 Hz, 2 H) 8.77 (s, 1 H) 8.83 (s, 1 H) 12.29 (s, 1 H) MS (ESI(+)) m/e 380.0 (M+H)+.
    • Example 197 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea
  • The desired product was prepared by substituting Example 195A for Example 1A and N-(2-fluorophenyl)'N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.98-7.06 (m, 1 H) 7.14 (dd, J=11.2, 7.8 Hz, 1 H) 7.16 (dt, J=7.5, 1.4 Hz, 1 H) 7.25 (ddd, J=11.5, 8.1,1.4 Hz, 1 H) 7.33-7.38 (m, 1 H) 7.39 (d, J=8.5 Hz, 2 H) 7.59 (d, J=8.5 Hz, 2 H) 8.17 (td, J=8.3, 1.7 Hz, 1 H) 8.61 (d, J=2.7 Hz, 1 H) 9.23 (s, 1 H) 11.99-12.62 (br. s., 1 H) MS (ESI(+)) m/e 380.0 (M+H)+.
    • Example 198 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea
  • The desired product was prepared by substituting Example 195A for Example 1A and N-(3-fluoro-4-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.17 (d, J=1.4 Hz, 3 H) 6.73 (dd, J=7.8, 4.1 Hz, 1 H) 7.05 (dd, J=8.3, 2.2 Hz, 1 H) 7.13 (dd, J=11.2, 7.8 Hz, 1 H) 7.17 (t, J=8.7 Hz, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.45 (dd, J=12.5, 2.0 Hz, 1 H) 7.58 (d, J=8.5 Hz, 2 H) 8.84 (s, 1 H) 8.86 (s, 1 H) 12.11-12.41 (br. s., 1 H) MS (ESI(+)) m/e 394.1 (M+H)+.
    • Example 199 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared by substituting Example 195A for Example 1A and N-phenyl-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.74 (dd, J=7.8, 4.4 Hz, 1 H) 6.98 (t, J=7.3 Hz, 1 H) 7.13 (dd, J=11.2, 7.8 Hz, 1 H) 7.26-7.32 (m, 2 H) 7.37 (d, J=8.5 Hz, 2 H) 7.46-7.49 (m, 2 H) 7.59 (d, J=8.5 Hz, 2 H) 8.74 (s, 1 H) 8.84 (s, 1 H) 11.99-12.59 (br. s., 1 H) MS (ESI(+)) m/e 362.0 (M+H)+.
    • Example 200 N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide Example 200A N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}-1,1,1-trifluoromethanesulfonamide
  • The desired product was prepared by substituting trifluoromethanesulfonic anhydride for methanesulfonyl chloride in Example 170B.
    • Example 200B N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
  • The desired product was prepared by substituting Example 200A and Example 1B for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 3.65 (q, J=6.1 Hz, 2 H) 4.24 (t, J=5.3 Hz, 2 H) 6.73 (d, J=7.8 Hz, 1 H) 6.80 (d, J=6.8 Hz, 1 H) 6.85 (d, J=7.8 Hz, 1 H) 7.16 (t, J=7.6 Hz, I H) 7.25 (d, J=8.5 Hz, 1 H) 7.31 (s, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.63 (s, 1 H) 8.78 (s, 1 H) 9.52 (t, J=5.6 Hz, 1 H) 11.83 (s, 1 H) MS (ESI(+)) m/e 549.1 (M+H)+.
    • Example 201 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 6.80-6.87 (m, 2 H) 7.13 (dd, J=11.4, 8.3 Hz, 1 H) 7.26-7.40 (m, 4 H) 8.04 (dd, J=8.1, 1.7 Hz, 1 H) 8.32 (t, J=8.5 Hz, 1 H) 9.04 (d, J=2.4 Hz, 1 M 9.16 (d, J=2.7 Hz, 1 H) 11.90 (s, 1 H) MS (ESI(+)) m/e 394.2 (M+H)+.
    • Example 202 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting N-(4-fluoro-3-trifluoromethylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.83 (dd, J=5.8, 2.3 Hz, 1 H) 7.27-7.34 (m, 2 H) 7.40-7.48 (m, 3 H) 7.61 (d, J=8.8 Hz, 2 H) 7.63-7.69 (m, 1 H) 8.03 (dd, J=6.4, 2.7 Hz, 1 H) 8.99 (s, 1 H) 9.13 (s, 1 H) 11.94 (s, 1 H) MS (ESI(+)) m/e 430.0 (M+H)+.
    • Example 203 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting N-(2-fluoro-3-trifluoromethylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.85 (dd, J=5.8, 2.0 Hz, 1 H) 7.29-7.39 (m, 4 H) 7.43 (d, J=8.5 Hz, 2 H) 7.62 (d, J=8.5 Hz, 2 H) 8.45-8.50 (m, 1 H) 8.90 (d, J=2.7 Hz, 1 H) 9.31 (s, 1 H) 12.01 (m, 1 H) MS (ESI(+)) m/e 430.1 (M+H)+.
    • Example 204 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(4-bromo-2-fluorophenyl)urea
  • The desired product was prepared by substituting N-(4-bromo-2-fluorophenyl)-N'-[4-(4,4,5,5-tetxamethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.83 (dd, J=5.8, 2.0 Hz, 1 H) 7.30 (d, J=0.7 Hz, 1 H) 7.31 (dd, J=13.2, 8.1 Hz, 1 H) 7.37 (ddd, J=8.8, 2.0, 1.4 Hz, 1 H) 7.42 (d, J=8.8 Hz, 2 H) 7.56-7.61 (m, 3 H) 8.16 (t, J=8.8 Hz, 1 H) 8.71 (d, J=2.4 Hz, 1 H) 9.25 (s, 1 H) 11.97 (s, 1 H) MS (ESI(+)) m/e 440.0, 440.9 (M+H)+.
    • Example 205 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(5-fluoro-2-methylphenyl)urea
  • The desired product was prepared by substituting N-(5-fluoro-2-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 3 H) 6.76 (td, J=8.5, 2.7 Hz, 1 H) 6.87 (dd, J=6.1, 1.7 Hz, 1 H) 7.16-7.24 (m, 1 H) 7.30-7.38 (m, 2 H) 7.43 (d, J=8.5 Hz, 2 H) 7.62 (d, J=8.5 Hz, 2 H) 7.87 (dd, J=12.2, 2.7 Hz, 1 H) 8.12 (s, 1 H) 9.34 (s, 1 H) 11.94-12.25 (br. s., 1 H) MS (ESI(+)) m/e 376.1 (M+H)+.
    • Example 206 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting N-(4-fluoro-3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J=1.7 Hz, 3 H) 6.84 (dd, J=6.1, 1.7 Hz, 1 H) 7.06 (t, J=9.2 Hz, 1 H) 7.25-7.34 (m, 3 H) 7.37-7.41 (m, 3 H) 7.59 (d, J=8.5 Hz, 2 H) 8.69 (s, 1 H) 8.84 (s, 1 H) 11.86-12.20 (br. s., 1 H) MS (ESI(+)) m/e 376.1 (M+H)+.
    • Example 207 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl-phenyl}-N'-phenylurea Example 207A 2-fluoro-6-iodo-3-(3-morpholin-4-ylpropoxy)benzonitrile
  • The desired product was prepared by substituting 3-(4-morphoiinyl)-propan-1-ol for 2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+)) m/e 391 (M+H)+.
    • Example 207B 4-(4-aminophenyl)-7-(3-morpholin-4-ylpropoxy)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 207A for Example 15E in Examples 15F-G.
    • Example 207C N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-phenylurea
  • The desired product was prepared by substituting Example 207B and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2 H) 3.08-3.20 (m, 4 H) 3.51-3.53 (m, 2 H) 3.65-3.70 (m, 2 H) 4.02-4.05 (m, 2 H) 4.24 (t, J=5.9 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.82 (d, J=7.8 Hz, 1 H) 6.98 (t, J=7.3 Hz, 1 H) 7.27-7.31 (m, 2 H) 7.35 (d, J=8.4 Hz, 2 H) 7.48 (d, J=7.8 Hz, 2 H) 7.57 (d, J=8.4 Hz, 2 H) 8.76 (s, 1 H) 8.84 (s, 1H) 9.68 (s, 1 H) 11.86 (s, I H) MS (ESI(+)) m/e 487.2 (M+H)+.
    • Example 208 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl)phenyl}-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 207 for Example 15G in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2 H) 3.08-3.18 (m, 4 H) 3.51-3.53 (m, 2 H) 3.65-3.70 (m, 2 H) 4.02-4.05 (m, 2 H) 4.23 (t, J=5.8 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.78 (dt, J=8.1, 2.5 Hz, 1 H) 6.82 (d, J=7.8 Hz, 1 H) 7.15 (dd, J=8.1, 1.3 Hz, 1 H) 7.31 (dd, J=15.3, 8.4 Hz, 1 H) 7.36 (d, J=8.7 Hz, 2 H) 7.52 (dt, J=11.9, 2.2 Hz, 1 H) 7.57 (d, J=8.7 Hz, 2 H) 8.96 (s, 1 H) 9.06 (s, 1 H) 9.71 (s, 1 H) 11.86 (s, 1 H) MS (ESI(+)) m/e 505.1 (M+H)+.
    • Example 209 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 207B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.19-2.24 (m, 2 H) 2.28 (s, 3 H) 3.08-3.18 (m, 2 H) 3.42-3.45 (m, 2 H) 3.50-3.55 (m, 2 H) 3.68-3.72 (m, 2 H) 4.03-4.08 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.75 (d, J=7.8 Hz, 1 H) 6.80-6.84 (m, 1 H) 6.84 (d, J=7.8 Hz, 1 H) 7.11 (dd, J=11.2, 8.4 Hz, 1 H) 7.37 (d, J=8.4 Hz, 2 H) 7.58 (d, J=8.4 Hz, 2 H) 7.99 (dd, J=7.8, 1.9 Hz, 1 H) 8.56 (d, J=2.5 Hz, 1 H) 9.24 (s, 1 H) 9.76-10.28 (br. s., 1 H) MS (ESI(+)) m/e 519.2 (M+H)+.
    • Example 210 N-(4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 207B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.19-2.23 (m, 2 H) 2.29 (s, 3 H) 3.08-3.17 (m, 2 H) 3.43-3.51 (m, 4 H) 3.66-3.70 (m, 2 H) 4.02-4.05 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.80 J=8.1 Hz, 1 H) 6.82 J=7.8 Hz, 1 H) 7.16 (t, J=7.6 Hz, 1 H) 7.26 (d, J=8.1 Hz, 1 H) 7.32 (s, 1 H) 7.35 (d, J=8.4 Hz, 2 H) 7.57 (d, J=8.4 Hz, 2 H) 8.70 (s, 1 H) 8.84 (s, 1 H) 9.72 (s, 1 H) 11.88 (s, 1 H) MS (ESI(+)) m/e 501.2 (M+H)+.
    • Example 211 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 207B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.24 (m, 2 H) 3.08-3.18 (m, 2 H) 3.42-3.45 (m, 2 H) 3.51-3.57 (m, 2 H) 3.65-3.71 (m, 2 H) 4.02-4.05 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.73 (d, J=7.5 Hz, 1 H) 6.83 (d, J=7.8 Hz, 1 H) 7.37-7.41 (m, 3 H) 7.49-7.53 (m, 1 H) 7.59 (d, J=8.7 Hz, 2 H) 8.64 (dd, J=7.3, 2.0 Hz, 1 H) 8.96 (d, J=2.8 Hz, 1 H) 9.32 (s, 1 H) 9.77 (s, 1 H) 11.92 (s, 1 H) MS (ESI(+)) m/e 573.1 (M+H)+.
    • Example 212 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 207B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2 H) 3.08-3.18 (m, 4 H) 3.66-3.70 (m, 4 H) 4.02-4.05 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.73 (d, J=7.8 Hz, 1 H) 6.82 (d, J=7.8 Hz, 1 H) 7.01-7.03 (m, 1 H) 7.29-7.33 (m, 2 H) 7.36 (d, J=8.4 Hz, 2 H) 7.58 (d, J=8.7 Hz, 2 H) 7.74 (s, 1 H) 9.00 (s, 1 H) 9.07 (s, 1 H) 9.74 (s, 1 H) 11.89 (s, 1 H) MS (ESI(+)) m/e 521.1 (M+H)+.
    • Example 213 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(trifruoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 207B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.24 (m, 2 H) 3.08-3.19 (m, 4 H) 3.42-3.44 (m, 2 H) 3.66-3.70 (m, 2 H) 4.02-4.04 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.74 (d, J=7.8 Hz, 1 H) 6.83 (d, J=7.8 Hz, 1 H) 7.32 (d, J=7.8 Hz, 1 H) 7.37 (d, J=8.4 Hz, 2 H) 7.52 (t, J=8.0 Hz, 1 H) 7.59-7.61 (m, 3 H) 8.05 (s, 1 H) 9.10 (s, 1 H) 9.28 (s, 1 H) 9.78 (s, 1 H) 11.94 (s, 1 H) MS (ESI(+)) m/e 555.2 (M+H)+.
    • Example 214 N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
  • The desired product was prepared by substituting Example 200A for Example 1A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 3.65 (q, J=4.9 Hz, 2 H) 4.24 (t, J=5.3 Hz, 2 H) 6.73 (d, J=7.8 Hz, 1 H) 6.78-6.82 (m, 1 H) 6.84 (d, J=7.5 Hz, 1 H) 7.11 (dd, J=11.4, 8.3 Hz, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.01 (dd, J=8.0, 2.2 Hz, 1 H) 8.52 (d, J=2.7 Hz, 1 H) 9.17 (s, 1 H) 9.52 (t, J=5.8 Hz, 1 H) 11.79 (s, 1 H) MS (ESI(+)) 567.0 m/e (M+H)+.
    • Example 215 N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
  • The desired product was prepared by substituting Example 200A and N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.65 (q, J=5.3 Hz, 2 H) 4.23 (t, J=5.3 Hz, 2 H) 6.71 (d, J=7.8 Hz, 1 H) 6.78 (td, J=8.5, 2.0 Hz, 1 H) 6.83 (d, J=7.8 Hz, 1 H) 7.13 (m, 1 H) 7.30 (m, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.44-7.54 (m, 1 H) 7.57 (d, J=8.5 Hz, 2 H) 8.86 (s, 1 H) 8.95 (s, 1 H) 9.52 (t, J=5.3 Hz, 1 H) 11.72 (s, 1 H) MS (ESI(-)) m/e 550.9 (M-H)-.
    • Example 216 N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide Example 216A N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide
  • The desired product was prepared by substituting phenylsulfonyl chloride for methanesulfonyl chloride in Example 170B. MS (ESI(+)) m/e 459 (M+H)+.
    • Example 216B N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide
  • The desired product was prepared by substituting Example 216A and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 3.26 (q, J=5.6 Hz, 2 H) 4.08 (t, J=5.6 Hz, 2 H) 6.67 (d, J=7.8 Hz, 1 H) 6.70 (d, J=7.8 Hz, 1 H) 6.79-6.82 (m, 1 H) 7.11 (dd, J=11.2, 8.4 Hz, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.55 (t, J=7.6 Hz, 2 H) 7.56 (d, J=8.5 Hz, 2 H) 7.61 (t, J=7.2 Hz, 1 H) 7.78 (t, J=6.1 Hz, 1 H) 7.84 (d, J=7.2 Hz, 2 H) 8.00 (dd, J=8.0,1.7 Hz, 1 H) 8.50 (d, J=2.5 Hz, 1 H) 9.16 (s, 1 H) 11.84 (s, 1 H) MS (ESI(-)) m/e 573.2 (M-H)-.
    • Example 217 N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide
  • The desired product was prepared by substituting Example 216A and N-(3-trifluoromethylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (500 MHz, DMSO-D6) δ ppm 3.26 (q, J=5.8 Hz, 2 H) 4.10 (t, J=5.6 Hz, 2 H) 6.70 (d, J=7.8 Hz, 1 H) 6.73 (d, J=7.8 Hz, 1 H) 7.32 (d, J=7.5 Hz, 1 H) 7.37 (d, J=8.4 Hz, 2 H) 7.51-7.63 (m, 7 H) 7.78 (t, J=6.1 Hz, 1 H) 7.84 (d, J=8.7 Hz, 2 H) 8.04 (s, 1 H) 8.93 (s, 1 H) 9.11 (s, 1 H) 12.01 (s, 1 H) MS (ESI(+)) m/e 611.1 (M+H)+.
    • Example 218 N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide
  • The desired product was prepared by substituting Example 216A and N-(3-fluorophenyl)-N'. [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (500 MHz, DMSO-D6) δ ppm 3.26 (q, J=5.6 Hz, 2 H) 4.09 (t, J=5.6 Hz, 2 H) 6.70 (d, J=7.8 Hz, 1 H) 6.73 (d, J=7.8 Hz, 1 H) 6.79 (td, J=8.4, 1.9 Hz, 1 H) 7.14 (dd, J=8.3, 1.1 Hz, 1 H) 7.29-7.34 (m, I H) 7.37 (d, J=8.7 Hz, 2 H) 7.49-7.58 (m, 5 H) 7.61 (t, J=7.3 Hz, 1 H) 7.78 (t, J=6.1 Hz, 1 H) 7.83-7.85 (m, J=8.4 Hz, 2 H) 8.88 (s, 1 H) 8.97 (s, 1 H) 12.00 (s, 1 H) MS (ESI(-)) m/e 559.0 (M-H)-.
    • Example 219 N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide
  • The desired product was prepared by substituting Example 216A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.26 (q, J=5.6 Hz, 2 H) 4.10 (t, J=5.6 Hz, 2 H) 6.70-6.75 (m, 2 H) 7.03 (td, J=4.3, 2.2 Hz, 1 H) 7.27-7.32 (m, 2 H) 7.37 (d, J=8.5 Hz, 2 H) 7.52-7.64 (m, 5 H) 7.74-7.75 (m, 1 H) 7.78-7.85 (m, 3 H) 8.92 (s, 1 H) 8.98 (s, 1 H) 12.09 (s, 1 H) MS (ESI(+)) m/e 577.0 (M+H)+.
    • Example 220 N-(4-{3-amino-7-[(isopropylamino)methy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 220A 2-fluoro-3-formyl-6-iodobenzonitrile
  • LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a stirred solution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol) in THF (200 mL) at-78 °C, and the mixture was stirred for 1h. Methyl formate (5.0 mL, 81.0 mmol) was added via syringe and the resulting mixture was stirred at -78 °C for 30 min then at rt for 1h. H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-25% EtOAc/hexanes to give the desired product (8.01 g). MS (ESI(+)) m/e 274.9 (M+H)+.
    • Example 220B 2-fluoro-6-iodo-3-[(isopropylamino)methyl]benzonitrile
  • A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 mL) was treated with isopropylamine (0.31 m, 3.6 mmol) and sodium cyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirred overnight at rt. HOAc (1 mL) was added and the reaction was stirred for 5h, then treated with 1N NaOH and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 8% MeOH/CH2Cl2 to give the desired product (372 mg). MS (ESI(+)) m/e 318.9 (M+H)+.
    • Example 220C 4-iodo-7-[(isopropylamino)methyl]-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 220B for 2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 330.9 (M+H)+.
    • Example 220D N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 220C and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.4 Hz, 6 H) 2.28 (s, 3 H) 3.39-3.51 (m, 1 H) 4.39 (t, J=6.1 Hz, 2 H) 6.79-6.84 (m, 1 H) 6.90 (d, J=7.1 Hz, 1 H) 7.12 (dd, J=11.4, 8.3 Hz, 1 H) 7.39-7.45 (m, 3 H) 7.61 (d, J=8.5 Hz, 2 H) 7.99 (dd, J=7.8, 2.0 Hz, 1 H) 8.55 (d, J=2.4 Hz, 1 H) 8.65-8.73 (m, 1 H) 9.25 (s, 1 H) 12.03 (s, 1 H) MS (ESI(+)) m/e 447.1 (M+H)+.
    • Example 221 N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 220C and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.8 Hz, 6 H) 3.37-3.49 (m, 1 H) 4.38 (t, J=5.9 Hz, 2 H) 6.90 (d, J=7.5 Hz, 1 H) 7.03 (dt, J=6.4, 2.4 Hz, 1 H) 7.28-7.35 (m, 2 H) 7.39-7.45 (m, 3 H) 7.62 (d, J=8.5 Hz, 2 H) 7.74-7.75 (m, 1 H) 8.63-8.73 (m, 2 H) 9.03 (s, 1 H) 9.04 (s, 1 H) 12.03 (s, 1 H) MS (ESI(+)) m/e 449.1 (M+H)+.
    • Example 222 N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 220C and N-(3-trifluoromethylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for
  • Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.4 Hz, 6 H) 3.39-3.51 (m, 1 H) 4.39 (t, J=5.8 Hz, 2 H) 6.91 (d, J=7.1 Hz, 1 H) 7.32 (d, J=7.5 Hz, 1 H) 7.39-7.45 (m, 3 H) 7.53 (t, J=8.0 Hz, 1 H) 7.59-7.66 (m, 3 H) 8.05 (s, 1 H) 8.67-8.73 (m, 2 H) 9.14 (s, 1 H) 9.28 (s, 1 H) 12.05 (s, 1 H) MS (ESI(-)) m/e 481.0 (M-H)-.
    • Example 223 N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 220C and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.4 Hz, 6 H) 2.29 (s, 3 H) 3.39-3.51 (m, 1 H) 4.36-4.40 (m, 2 H) 6.80 (d, J=7.8 Hz, 1 H) 6.90 (d, J=7.1 Hz, 1 H) 7.17 (t, J=7.8 Hz, 1 H) 7.26 (d, J=8.5 Hz, I H) 7.32 (s, 1 H) 7.39 (d, J=8.8 Hz, 2 H) 7.44 (d, J=7.5 Hz, 1 H) 7.62 (d, J=8.8 Hz, 2 H) 8.69 (m, 2 H) 8.75 (s, 1 H) 8.94 (s, I H) 12.03 (s, 1 H) MS (ESI(+)) m/e 429.1 (M+H)+.
    • Example 224 N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 220C and N-(4-fluoro-3-methylphenyl)N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.4 Hz, 6 H) 2.22 (d, J=1.7 Hz, 3 H) 3.39-3.51 (m, 1 H) 4.36-4.40 (m, 2 H) 6.90 (d, J=7.1 Hz, 1 H) 7.06 (t, J=9.2 Hz, 1 H) 7.28 (ddd, J=8.4, 4.8, 3.1 Hz, 1 H) 7.37-7.45 (m, 4 H) 7.61 (d, J=8.5 Hz, 2 H) 8.64-8.74 (m, 2 H) 8.79 (s, 1 H) 8.95 (s, 1 H) 12.04 (s, 1 H) MS (ESI(+)) m/e 447.1 (M+H)+.
    • Example 225 N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 225A 2-fluoro-3-(hydroxymethyl)-6-iodobenzonitrile
  • A solution of Example 220A (5.0 g, 18 mmol) in MeOH (100 mL) at 0 °C was treated with NaBH4 (822 mg, 22 mmol) and the mixture was stirred for 1 h at 0 °C. Acetone was added and the mixture was stirred for 5 min, then concentrated to dryness. The residue was partitioned between H2O and EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 3:2 hexanes/EtOAc to give the desired product (3.14 g). Rf = 0.38 (3:2 hexane :EtOAc).
    • Example 225B 3-[(4-chlorophenoxy)methyl]-2-fluoro-6-iodobenzonitrile
  • The desired product was prepared by substituting Example 225A and 4-chlorophenol for Example 68A and 2-(4-morpholinyl)ethanol, respectively, in Example 75A. Additionally, diisopropyl azodicarboxylate was substituted for DEAD. MS (ESI(-)) m/e 385.8 (M-H)-.
    • Example 225C 7-[(4-chlorophenoxy)methyl]-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 225B for 2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 399.9 (M+H)+.
    • Example 225D N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 225C for Example 1A and in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 5.33 (s, 2 H) 6.79-6.83 (m, 2 H) 7.09 (d, J=9.2 Hz, 2 H) 7.06-7.15 (m, 1 H) 7.33-7.38 (m, 3 H) 7.41 (d, J=8.5 Hz, 2 H) 7.60 (d, J=8.5 Hz, 2 H) 8.01 (dd, J=7.8, 2.0 Hz, 1 H) 8.54 (d, J=2.7 Hz, 1 H) 9.22 (s, 1 H) 12.00 (s, 1 H) MS (ESI(+)) m/e 516.1 (M+H)+.
    • Example 226 N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 226C and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.33 (s, 2 H) 6.82 (d, J=7.5 Hz, 1 H) 7.01-7.05 (m, 1 H) 7.08 (d, J=8.8 Hz, 2 H) 7.28-7.32 (m, 2 H) 7.33-7.38 (m, 3 H) 7.41 (d, J=8.8 Hz, 2 H) 7.60 (d, J=8.8 Hz, 2 H) 7.73-7.74 (m, 1 H) 8.93 (s, 1 H) 8.96 (s, 1 H) 12.01 (s, 1 H) MS (ESI(+)) m/e 518.5 (M+H)+.
    • Example 227 N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 225C and N-(3-trifluoromethylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.32 (s, 2 H) 6.82 (d, J=7.1 Hz, 1 H) 7.08 (d, J=8.8 Hz, 2 H) 7.31-7.37 (m, 4 H) 7.41 (d, J=8.5 Hz, 2 H) 7.53 (t, J=8.0 Hz, 1 H) 7.59-7.63 (m, 3 H) 8.04 (s, 1 H) 8.96 (s, 1 H) 9.11 (s, 1 H) 11.96 (s, 1 H) MS (ESI(+)) m/e 522.0 (M+H)+.
    • Example 228 N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 225C and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 5.33 (s, 2 H) 6.80 (d, J=7.5 Hz, 1 H) 6.83 (d, J=7.1 Hz, 1 H) 7.08 (d, J=8.8 Hz, 2 H) 7.17 (t, J=7.8 Hz, 1 H) 7.25 (d, J=8.5 Hz, 1 H) 7.32 (s, 1 H) 7.33-7.41 (m, 5 H) 7.60 (d, J=8.8 Hz, 2 H) 8.65 (s, 1 H) 8.82 (s, 1 H) 12.08 (s, 1 H) MS (ESI(+)) m/e 498.1 (M+H)+.
    • Example 229 N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 225C and N-(4-fluoro-3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted for DME/water as solvent. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J=1.7 Hz, 3 H) 5.33 (s, 2 H) 6.83 (d, J=7.1 Hz, 1 H) 7.01-7.11 (m, 3 H) 7.25-7.31 (m, 1 H) 7.33-7.41 (m, 6 H) 7.59 (d, J=8.8 Hz, 2 H) 8.68 (s, 1 H) 8.82 (s, 1 H) 12.05 (s, 1 H) MS (ESI(+)) m/e 516.1 (M+H)+.
    • Example 230 N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 230A 2-fluoro-6-iodo-3-[3-(1H-pyrrol-1-yl)propoxy]benzonitrile
  • The desired product was prepared by substituting 3-pyrrol-1-yl-propan-1-ol for 2-(4-morpholinyl)ethanol in Example 75A.
    • Example 230B 4-iodo-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 230A for 2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 383 (M+H)+.
    • Example 230C N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 230B for Example 1A in Example 5B. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.14-2.23 (m, 2 H) 2.27 (s, 3 H) 4.01 (t, J=6.1 Hz, 2 H) 4.19 (t, J=6.9 Hz, 2 H) 4.31 (s, 2 H) 5.97 (t, J=2.2 Hz, 2 H) 6.66 (d, J=7.5 Hz, 1 H) 6.71 (d, J=7.8 Hz, 1 H) 6.76 (t, J=2.2 Hz, 2 H) 6.78-6.81 (m, 1 H) 7.10 (dd, J=11.2, 8.4 Hz, 1 H) 7.35 (d, J=8.4 Hz, 2 H) 7.55 (d, J=8.4 Hz, 2 H) 7.99 (dd, J=8.0, 2.0 Hz, 1 H) 8.49 (d, J=2.2 Hz, 1 H) 9.14 (s, 1 H) 11.90 (s, 1 H) MS (ESI(+)) m/e 499.1 (M+H)+.
    • Example 231 1 4-(1H-indol-5-yl)-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 230B and indole-5-boronic acid for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.16-2.24 (m, 2 H) 4.02 (t, J=6.1 Hz, 2 H) 4.21 (t, J=6.6 Hz, 2 H) 4.29 (s, 2 H) 5.98 (t, J=2.0 Hz, 2 H) 6.47-6.49 (m, 1 H) 6.67 (d, J=7.5 Hz, 1 H) 6.72 (d, J=7.8 Hz, 1 H) 6.78 (t, J=2.0 Hz, 2 H) 7.14 (dd, J=8.3, 1.5 Hz, 1 H) 7.41 (t, J=2.7 Hz, 1 H) 7.49 (d, J=8.1 Hz, 1 H) 7.56 (s, 1 H) 11.19 (s, 1 H) 11.86 (s, 1 H). MS (ESI(+)) m/e 372.1 (M+H)+.
    • Example 232 N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 230B and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.16-2.24 (m, 2 H) 2.29 (s, 3 H) 4.02 (t, J=5.9 Hz, 2 H) 4.20 (t, J=6.8 Hz, 2 H) 5.98 (t, J=2.2 Hz, 2 H) 6.68 (d, J=7.8 Hz, 1 H) 6.74 (d, J=7.8 Hz, 1 H) 6.77 (t, J=2.0 Hz, 2 H) 6.80 (d, J=7.1 Hz, 1 H) 7.16 (t, J=7.6 Hz, 1 H) 7.25 (d, J=8.1 Hz, 1 H) 7.32 (s, 1 H) 7.35 (d, J=8.8 Hz, 2 H) 7.56 (d, J=8.8 Hz, 2 H) 8.63 (s, 1 H) 8.76 (s, 1 H) 12.05 (s, 1 H) MS (ESI(+)) m/e 481.1 (M+H)+.
    • Example 233 N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 230B and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.23 (m, 2 H) 4.01 (t, J=5.9 Hz, 2 H) 4.20 (t, J=6.8 Hz, 2 H) 4.33 (s, 2 H) 5.98 (t, J=2.2 Hz, 2 H) 6.66 (d, J=7.5 Hz, 1 H) 6.72 (d, J=7.8 Hz, 1 H) 6.77 (t, J=2.2 Hz, 2 H) 7.02 (dt, J=6.4, 2.2 Hz, 1 H) 7.28 (m, 2 H) 7.36 (d, J=8.5 Hz, 2 H) 7.56 (d, J=8.5 Hz, 2 H) 7.72-7.74 (m, 1 H) 8.85 (s, 1 H) 8.92 (s, 1 H) 11.93 (s, 1 H) MS (ESI(-)) m/e 499.3 (M-H)-.
    • Example 234 N[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide Example 234A N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}thiophene-2-sulfonamide
  • The desired product was prepared by substituting 2-thiophenesulfonyl chloride for methanesulfonyl chloride in Example 170B. MS (ESI(+)) m/e 465 (M+H)+.
    • Example 234B N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide
  • The desired product was prepared by substituting Example 234A for Example 1A in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 3.30-3.34 (m, 2 H) 4.14 (t, J=5.9 Hz, 2 H) 6.68 (d, J=7.5 Hz, 1 H) 6.74 (m, J=7.5 Hz, 1 H) 6.79-6.83 (m, 1 H) 7.11 (dd, J=11.4, 8.3 Hz, 1 H) 7.17 (dd, J=5.1, 3.7 Hz, 1 H) 7.36 (d, J=8.8 Hz, 2 H) 7.56 (d, J=8.8 Hz, 2 H) 7.65 (dd, J=3.7, 1.4 Hz, 1 H) 7.92-8.02 (m, 3 H) 7.98 (d, J=6.4 Hz, 1 H) 8.01 (dd, J=7.8, 2.0 Hz, 1 H) 8.51 (d, J=2.4 Hz, 1 H) 9.17 (s, 1 H) 11.84 (s, 1 H) MS (ESI(+)) m/e 580.6 (M+H)+.
    • Example 235 N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide
  • The desired product was prepared by substituting Example 234A and N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 3.33 (q, J=5.8 Hz, 2 H) 4.14 (t, J=5.8 Hz, 2 H) 6.66-6.84 (m, 3 H) 7.16 (t, J=7.8 Hz, 1 H) 7.17 (dd, J=5.1, 3.7 Hz, 1 H) 7.25 (d, J=8.8 Hz, 1 H) 7.31 (s, 1 H) 7.35 (d, J=8.5 Hz, 2 H) 7.56 (d, J=8.5 Hz, 2 H) 7.65 (dd, J=3.7, 1.4 Hz, 1 H) 7.93 (dd, J=5.1,1.4 Hz, 1 H) 7.97 (t, J=5.9 Hz, 1 H) 8.63 (s, 1 H) 8.77 (s, 1 H) 11.91 (s, 1 H) MS (ESI(+)) m/e 563.0 (M+H)+.
    • Example 236 N-(2-{[3-amino-4-(1H-indol-5-yl)-1H-indazol-7-yl]oxy}ethyl)thiophene-2-sulfonamide
  • The desired product was prepared by substituting Example 234A and indole-5-boronic acid for Example 1A and Example 5A, respectively, in Example 5B. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.33 (q, J=5.4 Hz, 2 H) 4.16 (t, J=5.6 Hz, 2 H) 6.49-6.49 (m, 1 H) 6.74 (d, J=7.8 Hz, 1 H) 6.78 (d, J=7.8 Hz, 1 H) 7.15 (dd, J=8.5, 1.7 Hz, 1 H) 7.18 (dd, J=4.8, 3.7 Hz, 1 H) 7.41 (t, J=2.7 Hz, 1 H) 7.49 (d, J=8.1 Hz, 1 H) 7.57 (d, J=1.4 Hz, 1 H) 7.65 (dd, J=3.7, 1.4 Hz, 1 H) 7.94 (dd, J=5.1, 1.4 Hz, 1 H) 7.98 (t, J=5.9 Hz, 1 H) 11.20 (s, 1 H) 11.98 (s, 1 H) MS (ESI(+)) m/e 454.0 (M+H)+.
    • Example 237 N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 237A 3-[3-(diethylamino)propoxy]-2-fluoro-6-iodobenzonitrile
  • The desired product was prepared by substituting 3-(diethylamino)-propan-1-ol for 2-(4-morpholinyl)ethanol in Example 75A.
    • Example 237B 4-(4-aminophenyl)-7-[3-(diethylamino)propoxy]-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 237A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H)+.
    • Example 237C N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 237B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.25 (t, J=7.3 Hz, 6 H) 2.11-2.20 (m, 2 H) 2.28 (s, 3 H) 3.16-2.35 (m, 4 H) 3.31-3.41 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.71 (d, J=7.5 Hz, 1 H) 6.79-6.84 (m, 2 H) 7.11 (dd, J=11.4, 8.3 Hz, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.00 (dd, J=7.8, 2.0 Hz, 1 H) 8.52 (d, J=2.4 Hz, 1 H) 9.07 (s, 1 H) 9.18 (s, 1 H) 11.93 (s, 1H) MS (APCI(+)) m/e 505.4 (M+H)+.
    • Example 238 N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 237B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.25 (t, J=7.29 Hz, 6 H) 2.11-2.20 (m, 2 H) 3.16-3.25 (m, 4 H) 3.34-3.14 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.71 (d, J=7.8 Hz, 1 H) 6.81 (d, J=7.8 Hz, 1 H) 7.03 (dt, J=6.4, 2.4 Hz, 1 H) 7.26-7.32 (m, 2 H) 7.36 (d, J=8.8 Hz, 2 H) 7.57 (d, J=8.8 Hz, 2 H) 7.73-7.74 (m, 1 H) 8.92 (s, 1 H) 8.98 (s, 1 H) 9.05 (s, 1 H) 11.92 (s, 1 H) MS (ESI(+)) m/e 506.9 (M+H)+.
    • Example 239 N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 23 7B and 1-isocyanate-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.24 (t, J=7.3 Hz, 6 H) 2.11-2.20 (m, 2 H) 3.16-3.25 (m, 4 H) 3.31-3.37 (m, 2 H) 4.24 (t, J=5.6 Hz, 2 H) 6.71 (d, J=7.8 Hz, 1 H) 6.81 (m, J=7.8 Hz, 1 H) 7.32 (d, J=7.1 Hz, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.50-7.61 (m, 4 H) 8.04 (s, 1 H) 8.95 (s, 1 H) 9.04 (s, 1 H) 9.13 (s, 1 H) 11.92 (s, 1 H) MS (ESI(+)) m/e 541.2 (M+H)+.
    • Example 240 N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 237B for Example 15G in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.25 (t, J=7.3 Hz, 6 H) 2.11-2.20 (m, 2 H) 3.16-3.24 (m, 4 H) 3.34-3.43 (m, 2 H) 4.24 (t, J=5.6 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.76-6.82 (m, 1 H) 6.81 (d, J=7.8 Hz, 1 H) 7.14 (ddd, J=8.1, 2.0, 0.7 Hz,1 1 H) 7.28-7.35 (m, 1 H) 7.36 (d, J=8.8 Hz, 2 H) 7.52 (dt, J=12.0, 2.3 Hz, 1 H) 7.57 (d, J=8.8 Hz, 2 H) 8.92 (s, 1 H) 9.01 (s, 1 H) 9.06 (s, 1 H) 11.94 (s, 1 H) MS (APCI(-))m/e 489.3 (M-H)-.
    • Example 241 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.37 (s, 2 H) 6.80-6.86 (m, 1 H) 7.26-7.35 (m, 4 H) 7.39 (dd, J=12.2, 1.7 Hz, 1 H) 7.54-7.56 (m, 2 H) 8.06 (s, 1 H) 8.26 (t, J=8.5 Hz, 1 H) 8.76 (d, J=2.4 Hz, 1 H) 9.47 (s, 1 H) 11.77 (s, 1 H) MS (ESI(+)) m/e 430.0 (M+H)+.
    • Example 242 N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.37 (s, 2 H) 6.83 (dd, J=4.4, 3.7 Hz, 1 H) 7.25-7.29 (m, 3 H) 7.38 (dd, J=12.0, 1.9 Hz, 1 H) 7.46 (t, J=9.8 Hz, 1 H) 7.61-7.66 (m, 1 H) 8.05 (dd, J=6.4, 2.7 Hz, 1 H) 8.23 (t, J=8.5 Hz, 1 H) 8.75 (d, J=1.7 Hz, 1 H) 9.45 (s, 1 H) 11.77 (s, 1 H) MS (ESI(+)) m/e 448.0 (M+H)+.
    • Example 243 N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea Example 243A 3-fluoro-1,1'-biphenyl-2-carbonitrile
  • The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 1A and phenylboronic acid for Example 1B in Example 1C. Additionally, toluene/EtOH/H2O (3:2:1) was substituted for DME/H2O as the solvent.
    • Example 243B 3-fluoro-4-iodo-1,1'-biphenyl-2-carbonitrile
  • A solution of Example 243A (6.8 g, 34.5 mmol) in THF (110 mL) at-78 °C under nitrogen atmosphere was treated dropwise with LDA (2.0 M solution in THF) and stirred for 1 h, then a solution of iodine in THF (30 mL) was added via cannula over about 10 min. The thick mixture was allowed to warm to rt and stirred for 1 h, then treated with saturated aqueous Na2S2O3 solution (10 mL). The mixture was concentrated to remove the THF, then H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/hexanes (1:7), and the resulting solid was triturated with hexanes and EtOAc to give the desired product (6.8 g). Rf = 0.44 (7:1 hexane :EtOAc)
    • Example 243C 3-fluoro-4-iodo-4'-nitro-1,1'-biphenyl-2-carbonitrile
  • A solution of Example 243B (2.77 g, 8.6 mmol) in 1,2-dichloroethane (50 mL) under nitrogen atmosphere was treated with nitronium tetrafluoroborate (85% technical grade, 2.0 g, 12.9 mmol) and the mixture was stirred for 3.5 h, at which time an additional portion of nitronium tetrafluoroborate (700 mg, 5.3 mmol) was added. The reaction was stirred for another 2 h, then poured over ice, and once melted the mixture was neutralized with sat. NaHCO3 solution. The mixture was extracted with EtOAc, and the extracts were washed with brine, dried (MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexanes/ EtOAc (4:1) to give the desired product (1.84 g). MS (ESI(-)) m/e 367.9 (M-H)+.
    • Example 243D 3-fluoro-4'-nitro-4-pyridin-3-yl-1,1'-biphenyl-2-carbonitrile
  • The desired product was prepared by substituting Example 243C and pyridine-3-boronic acid for Examples 1A and 1B, respectively, in Example 1C. Additionally, PdCl2(dppf) was used in place of Pd(PPh3)4. MS (ESI(+)) m/e 320.0 (M+H)+.
    • Example 243E 4-(4-aminophenyl)-7-pyridin-3-yl-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 243D for 2-fluoro-6-iodobenzonitrile in Example 1A. In addition to pyrazole cyclization, nitro reduction was also accomplished in this reaction. MS (ESI(+)) m/e 302.0 (M+H)+.
    • Example 243F N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 243E and 1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.23 (d, J=1.7 Hz, 3 H) 6.97 (d, J=7.5 Hz, 1 H) 7.06 (t, J=9.2 Hz, 1 H) 7.29 (ddd, J=8.7, 4.5, 3.1 Hz, 1 H) 7.39 (dd, J=6.8, 2.8 Hz, 1 H) 7.43-7.47 (m, 3 H) 7.62 (d, J=8.5 Hz, 2 H) 7.69-7.80 (m, 1 H) 8.32 (d, J=7.8 Hz, 1 H) 8.67-8.80 (m, 1 H) 8.71 (s, 1 H) 8.87 (s, 1 H) 8.90-9.15 (m, 1 H) 11.81-12.42 (br. s., 1 H) MS (ESI(+)) m/e 453.1 (M+H)+.
    • Example 244 N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 243E and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.96 (d, J=7.5 Hz, 1 H) 7.02-7.05 (m, 1 H) 7.28-7.35 (m, 2 H) 7.44-7.47 (m, 3 H) 7.63 (d, J=8.8 Hz, 2 H) 7.66-7.72 (m, 1 H) 7.74-7.75 (m, 1 H) 8.27 (d, J=7.5 Hz, 1 H) 8.61-8.85 (m, 1 H) 8.93-9.04 (m, 3 H) 11.73-12.36 (br. s., 1 H) MS (ESI(+)) m/e 455.1 I (M+H)+.
    • Example 245 N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)pheny]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 243E and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.97 (d, J=7.1 Hz, 1 H) 7.33 (d, J=7.5 Hz, 1 H) 7.44-7.47 (m, 3 H) 7.53 (t, J=7.8 Hz, 1H) 7.60-7.70 (m, 4 H) 8.05 (s, 1 H) 8.26 (d, J=8.1 Hz, 1 H) 8.61-8.81 (m, 1 H) 8.89-9.08 (m, 2 H) 9.15 (s, 1 H) 11.79-12.29 (br. s., 1 H) MS (ESI(+)) m/e 489.1 (M+H)+.
    • Example 246 N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 243E and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 6.79-6.84 (m, 1 H) 6.96 (d, J=7.5 Hz, 1 H) 7.12 (dd, J=11.4, 8.3 Hz, 1 H) 7.44-7.47 (m, 3 H) 7.63 (d, J=8.8 Hz, 2 H) 7.65-7.73 (m, 1 H) 8.01 (dd, J=8.0, 1.9 Hz, 1 H) 8.26 (d, J=7.8 Hz, 1 H) 8.55 (d, J=2.4 Hz, 1 H) 8.63-8.82 (m, 1 H) 8.88-9.11 (m, 1 H) 9.24 (s, 1 H) 11.79-12.33 (br. s., 1 H) MS (ESI(+)) m/e 453.1 (M+H)+.
    • Example 247 N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 243E and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.95 (d, J=7.5 Hz, 1 H) 7.40-7.49 (m, 4 H) 7.61-7.70 (m, 4 H) 8.04 (dd, J=6.4, 2.7 Hz, 1H) 8.19-8.23 (m, 1 H) 8.67 (dd, J=4.8, 1.4 Hz, 1 H) 8.94-8.97 (m, 1 H) 9.00 (s, 1 H) 9.12 (s, 1 H) 12.02 (s, I H) MS (ESI(+)) m/e 507.1 (M+H)+.
    • Example 248 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea Example 248A 3-[3-(dimethylamino)propoxy]-2-fluoro-6-iodobenzonitrile
  • The desired product was prepared by substituting 3-(dimethylamino)-propan-1-ol for 2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+)) m/e 349 (M+H)+.
    • Example 248B 4-(4-aminophenyl)-7-[3-(dimethylamino)propoxy]-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 248A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 326 (M+H)+.
    • Example 248C N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 248B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2 H) 2.28 (s, 3 H) 2.86 (d, J=5.1 Hz, 6 H) 3.34-3.41 (m, 2 H) 4.22 (t, J=5.8 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.80 (d, J=7.1 Hz, 1 H) 6.82 (d, J=7.8 Hz, 1 H) 7.16 (t, J=7.8 Hz, 1 H) 7.25 (d, J=8.5 Hz, 1 H) 7.32 (s, 1 H) 7.34 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.68 (s, 1 H) 8.83 (s, 1 H) 9.40 (s, 1 H) 11.94 (s, 1 H) MS (ESI(+)) m/e 459.2 (M+H)+.
    • Example 249 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 248B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2 H) 2.28 (s, 3 H) 2.86 (d, J=4.8 Hz, 6 H) 3.34-3.42 (m, 2 H) 4.22 (t, J=5.9 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.79-6.83 (m, 2 H) 7.12 (dd, J=11.2, 8.5 Hz, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.00 (dd, J=8.0, 1.9 Hz, 1 H) 8.53 (d, J=2.4 Hz, 1 H) 9.19 (s, 1 H) 9.41 (s, 1 H) 11.94 (s, 1 H) MS (ESI(+)) m/e 477.1 (M+H)+.
    • Example 250 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 248B for Example 15G in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2 H) 2.86 (d, J=4.8 Hz, 6 H) 3.34-3.41 (m, 2 H) 4.22 (t, J=5.9 Hz, 2 H) 6.73 (d, J=7.5 Hz, 1 H) 6.79 (td, J=8.6, 2.5 Hz, 1 H) 6.83 (d, J=7.8 Hz, 1 H) 7.14 (ddd, J=8.1, 2.0, 1.0 Hz, 1 H) 7.26-7.37 (m, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.52 (dt, J=12.0, 2.3 Hz, 1 H) 7.58 (d, J=8.5 Hz, 2 H) 8.98 (s, 1 H) 9.07 (s, 1 H) 9.44 (s, 1 H) 11.99 (s, 1 H) MS (ESI(+)) m/e 463.2 (M+H)+.
    • Example 251 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 248 and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2 H) 2.86 (d, J=4.8 Hz, 6 H) 3.34-3.41 (m, 2 H) 4.22 (t, J=5.8 Hz, 2 H) 6.73 (d, J=7.8 Hz, 1 H) 6.82 (d, J=7.8 Hz, 1 H) 7.03 (ddd, J=6.1, 3.1, 2.4 Hz, 1 H) 7.27-7.32 (m, 2 H) 7.36 (d, J=8.5 Hz, 2 H) 7.58 (d, J=8.5 Hz, 2 H) 7.73-7.75 (m, 1 H) 8.98 (s, 1 H) 9.04 (s, 1 H) 9.41 (s, 1 H) 11.96 (s, 1 H) MS (ESI(+)) m/e 479.1 (M+H)+.
    • Example 252 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 248B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2 H) 2.86 (d, J=4.8 Hz, 6 H) 3.34-3.41 (m, 2 H) 4.22 (t, J=5.9 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.82 (d, J=7.8 Hz, 1 H) 7.32 (d, J=7.5 Hz, 1 H) 7.36 (d, J=8.8 Hz, 2 H) 7.50-7.61 (m, 4 H) 8.05 (s, 1 H) 8.98 (s, 1 H) 9.16 (s, 1 H) 9.38 (s, 1 H) 11.92 (s, 1 H) MS (ESI(+)) me/ 513.1 (M+H)+.
    • Example 253 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 248B and 1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.19 (m, 2 H) 2.22 (d, J=1.7 Hz, 3 H) 2.86 (d, J=5.1 Hz, 6 H) 3.34-3.41 (m, 2 H) 4.22 (t, J=5.9 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1 H) 6.81 (d, J=7.8 Hz, 1 H) 7.05 (t, J=9.2 Hz, 1 H) 7.28 (ddd, J=8.8, 4.1, 2.7 Hz, 1 H) 7.33-7.39 (m, 3 H) 7.56 (d, J=8.5 Hz, 2 H) 8.72 (s, 1 H) 8.83 (s, 1 H) 9.41 (s, 1 H) 11.95 (s, 1 H) MS (ESI(+)) m/e 477.2 (M+H)+.
    • Example 254 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 207B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2 H) 3.06-3.19 (m, 4 H) 3.42-3.46 (m, 2 H) 3.65-3.70 (m, 2 H) 4.00-4.07 (m, 2 H) 4.24 (t, J=5.8 Hz, 2 H) 6.73 (d, J=7.8 Hz, 1 H) 6.83 (d, J=7.8 Hz, 1 H) 7.16 (ddd, J=8.1, 1.9, 0.9 Hz, 1 H) 7.25 (t, J=8.1 Hz, 1 H) 7.32-7.38 (m, 3 H) 7.58 (d, J=8.7 Hz, 2 H) 7.88 (t, J=1.9 Hz, 1 H) 8.99 (s, 1 H) 9.04 (s, 1 H) 9.73 (s, 1 H) 11.91 (s, 1 H) MS (ESI(+)) m/e 565.1, 567.1 (M+H)+.
    • Example 255 N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(3-methylphenyl)urea Example 255A 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
  • The desired product was prepared by substituting 4-bromo-3-fluoro-phenylamine for Example 149A in Example 149B. The mixture was heated at 85 °C overnight and the desired product was purified by flash chromatography using 30% ethyl acetate in hexanes. MS (ESI(+) m/e 238 (M+H)+.
    • Example 255B N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 255A and 1-isocyanato-3-methylbenzene for 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A. MS (ESI(+) m/e 371 (M+H)+.
    • Example 255C N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 255B for Example 1B in Example 1C. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.29 (s, 3H), 6.81-6.85 (m, 2H), 7.18 (t, J=7.83 Hz, 1H), 7.25 (d, J=1.84 Hz, 1H), 7.27 (d, J=1.84 Hz, 1H), 7.30-7.34 (m, 4H), 7.64 (dd, J=12.73, 1.99 Hz, 1H), 8.74 (s, 1H), 9.04 (s, 1H); MS (ESI(+) m/e 376 (M+H)+.
    • Example 256 N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 255A for 4-bromo-2-ethylaniline in Example 149A and then substituting the product for Example 1B in Example 1C. 1HNMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H), 7.02-7.05 (m, 1H), 7.08 (t, J=3.84 Hz, 1H), 7.32 (dd, J=11.20, 8.44 Hz, 1H), 7.43-7.45 (m, 1H), 7.52-7.57 (m, 3H), 7.85 (dd, J=12.43,1.69 Hz, 1H), 8.17 (d, J=7.98 Hz, 1H), 8.80 (d, J=2.15 Hz, 1H), 9.61 (s, 1H); MS (ESI(+) m/e 394 (M+H)+.
    • Example 257 N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 255A and 1-chloro-3-isocyanatobenzene for 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A and then substituting the product for Example 1B in Example 1C. 1H NMR (400 MHz, DMSO-D6) δ ppm 6.81 (dd, J=4.91, 2.46 Hz, 1H), 7.03-7.06 (m, 1H), 7.27-7.35 (m, 6H), 7.62 (dd, J=12.43, 1.99 Hz, 1H), 7.72 (t, J=1.99 Hz, 1H), 9.02 (s, 1H), 9.12 (s, 1H); MS (ESI(+) m/e 396 (M+H)+.
    • Example 258 N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 255A and 1-fluoro-4-isocyanato-2-methylbenzene for 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A and then substituting the product for Example 1B in Example 1C. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.22 (s, 3H), 6.87 (t, J=3.84 Hz, 1H), 7.06 (t, J=9.05 Hz, 1H), 7.27-7.38 (m, 6H), 7.63 (dd, J=12.58, 1.53 Hz, 1H), 8.79 (s, 1H), 9.07 (s, 1H); MS (ESI(+) m/e 394 (M+H)+.
    • Example 259 N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 255A and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A and then substituting the product for Example 1B in Example 1C. 1H NMR (400 MHz, DMSO-D6) δ ppm 6.89 (t, J=3.84 Hz, 1H), 7.28 (dd, J=8.44, 1.99 Hz, 1H), 7.34-7.38 (m, 3H), 7.42-7.45 (m, 1H), 7.50-7.54 (m, 1H), 7.66 (dd, J=12.43, 1.99 Hz, 1H), 8.61 (dd, J=7.21, 1.99 Hz, 1H), 9.03 (d, J=2.15 Hz, 1H), 9.54 (s, 1H); MS (ESI(+) m/e 448 (M+H)+.
    • Example 260 N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 255A and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A and then substituting the product for Example 1B in Example 1C. 1H NMR (400 MHz, DMSO-D6) δ ppm 6.84 (t, J=3.99 Hz, 1H), 7.29-7.36 (m, 4H), 7.46 (t, J=9.82 Hz, 1H), 7.62 (dd, J=12.73, 1.69 Hz, 1H), 7.68 (m, 1H), 8.02 (dd, J=6.60, 2.92 Hz, 1H), 9.21 (s, 2H); MS (ESI(+) m/e 448 (M+H)+.
    • Example 261 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea Example 261A 4-(4-aminophenyl)-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 95A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 226 (M+H)+.
    • Example 261B N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-isocyanato-3,5-dimethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6 H) 5.22 (s, 2 H) 6.63 (s, 1 H) 7.10 (s, 2 H) 7.14 (d, J=6.8 Hz, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.48 (d, J=8.1Hz, 1 H) 7.56-7.64 (m, 3 H) 8.57 (s, 1 H) 8.83 (s, 1 H) MS (ESI(+)) m/e 373.1 (M+H)+.
    • Example 262 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared by substituting Example 261A and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 6.99 (t, J=7.5 Hz, 1 H) 7.14 (d, J=7.1 Hz, 1 H) 7.30 (t, J=8.0 Hz, 2 H) 7.44 (d, J=8.5 Hz, 2 H) 7.46-7.50 (m, 3 H) 7.58 (dd, J=8.3, 7.3 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 8.74 (s, 1 H) 8.87 (s, 1 H) MS (ESI(+)) m/e 345.0 (M+H)+.
    • Example 263 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea
  • The desired product was prepared by substituting Example 261A and i-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3 H) 5.22 (s, 2 H) 7.10 (d, J=8.5 Hz, 2 H) 7.13 (d, J=6.8 Hz, 1 H) 7.36 (d, J=8.5 Hz, 2 H) 7.43 (d, J=8.5 Hz, 2 H) 7.48 (d, J=8.1 Hz, 1 H) 7.55-7.63 (m, 3 H) 8.62 (s, 1 H) 8.83 (s, 1 H) MS (ESI(+)) m/e 359.0 (M+H)+.
    Figure imgb0012
    • Example 264 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
  • The desired product was prepared by substituting Example 261A and 3-isocyanatobenzonitrile for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.14 (dd, J=7.1, 0.7 Hz, 1 H) 7.42-7.50 (m, 4 H) 7.51 (t, J=8.0 Hz, 1 H) 7.59 (dd, J=8.5, 7.5 Hz, 1 H) 7.64 (d, J=8.5 Hz, 2 H) 7.71 (ddd, J=8.2, 2.1, 1.2 Hz, 1 H) 8.00 (t, J=1.9 Hz, 1 H) 9.05 (s, 1 H) 9.09 (s, 1 H) MS (ESI(+)) m/e 370.0 (M+H)+.
    • Example 265 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 261A and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.14 (d, J=7.1 Hz, 1 H) 7.45 (d, J=8.5 Hz, 2 H) 7.45 (t, J=9.7 Hz, 1 H) 7.49 (dd, J=8.1, 0.7 Hz, 1 H) 7.59 (dd, J=8.5, 7.5 Hz, 1 H) 7.62-7.70 (m, 3 H) 8.03 (dd, J=6.4, 2.7 Hz, 1 H) 9.01 (s, 1 H) 9.11 (s, 1 H) MS (ESI(+)) m/e 431.0 (M+H)+.
    • Example 266 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.13-7.18 (m, 2 H) 7.26 (t, J=8.0 Hz, 1 H) 7.34 (ddd, J=8.1, 2.0, 1.4 Hz, 1 H) 7.44 (d, J=8.5 Hz, 2 H) 7.49 (dd, J=8.5, 0.9 Hz, 1 H) 7.59 (dd, J=8.5, 7.1 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 7.88 (t, J=1.9 Hz, 1 H) 8.95 (s, 1 H) 8.96 (s, 1 H) MS (ESI(+)) m/e 422.9, 424.8 (M+H)+.
    • Example 267 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.75 (s, 2 H) 7.03 (dt, J=6.4, 2.7 Hz, 1 H) 7.14 (dd, J=7.1, 0.7 Hz, 1 H) 7.28-7.35 (m, 2 H) 7.44 (d, J=8.5 Hz, 2 H) 7.48 (d, J=8.1 Hz, 1 H) 7.59 (dd, J=8.1, 7.5 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 7.73 (t, J=2.0 Hz, 1 H) 8.96 (app. s., 2 H) MS (ESI(+)) m/e 379.0 (M+H)+.
    • Example 268 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
  • The desired product was prepared by substituting Example 261A and 3-ethyl-1-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (t, J=7.5 Hz, 3 H) 2.59 (q, J=7.5 Hz, 2 H) 5.22 (s, 2 H) 6.84 (d, J=7.5 Hz, 1 H) 7.14 (d, J=7.1 Hz, 1 H) 7.19 (t, J=7.6 Hz, 1 H) 7.27 (d, J=7.8 Hz, 1 H) 7.34 (s, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.48 (d, J=8.1 Hz, 1 H) 7.56-7.64 (m, 3 H) 8.67 (s, 1 H) 8.84 (s, 1 H) MS (ESI(+)) m/e 373.0 (M+H)+.
    • Example 269 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 261A and 1-isocyanate-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.15 (d, J=7.1 Hz, 1 H) 7.44-7.50 (m, 3 H) 7.59 (dd, J=8.5, 7.1 Hz, 1 H) 7.63-7.71 (m, 6 H) 9.02 (s, 1 H) 9.18 (s, 1 H) MS (ESI(+)) m/e 413.0 (M+H)+.
    • Example 270 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-fluoro-5-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.17 (d, J=1.4 Hz, 3 H) 5.22 (s, 2 H) 7.05 (dd, J=8.3, 2.2 Hz, 1 H) 7.12-7.21 (m, 2 H) 7.42-7.50 (m, 4 H) 7.56-7.64 (m, 3 H) 8.84 (s, 1 H) 8.90 (s, 1 H) MS (ESI(+)) m/e 377.1 (M+H)+.
    • Example 271 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 261A for Example 15G in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 6.77-6.83 (m, 1 H) 7.13-7.18 (m, 2 H) 7.32 (td, J=8.1, 7.1 Hz, 1 H) 7.44 (d, J=8.8 Hz, 2 H) 7.48 (dd, J=8.5, 1.0 Hz, 1 H) 7.52 (dt, J=11.9, 2.4 Hz, 1 H) 7.59 (dd, J=8.1, 7.5 Hz, 1 H) 7.63 (d, J=8.8 Hz, 2 H) 8.94 (s, 1 H) 8.98 (s, 1 H) MS (ESI(+)) m/e 363.0 (M+H)+.
    • Example 272 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)urea
  • The desired product was prepared by substituting Example 261A and 1,3-difluoro-5-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2 H) 6.81 (tt, J=9.4, 2.3 Hz, 1 H) 7.14 (dd, J=7.1, 0.7 Hz, 1 H) 7.22 (dd, J=10.0, 2.3 Hz, 2 H) 7.45 (d, J=8.5 Hz, 2 H) 7.49 (dd, J=8.5, 0.7 Hz, 1 H) 7.59 (dd, J=8.5, 7.1 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 9.05 (s, 1 H) 9.16 (s, 1 H) MS (ESI(+)) m/e 381.0 (M+H)+.
    • Example 273 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea
  • The desired product was prepared by substituting Example 261A and 3-isocyanato-1-methoxybenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.74 (s, 3 H) 5.22 (s, 2 H) 6.57 (dd, J=8.0, 2.2 Hz, 1 H) 6.96 (dd, J=8.1, 1.4 Hz, 1 H) 7.14 (d, J=6.8 Hz, 1 H) 7.19 (t, J=8.1 Hz, 1 H) 7.21 (t, J=2.2 Hz, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.48 (d, J=7.8 Hz, 1 H) 7.58 (dd, J=8.1, 7.1 Hz, 1 H) 7.62 (d, J=8.5 Hz, 2 H) 8.75 (s, 1 H) 8.86 (s, 1 H) MS (ESI(+)) m/e 375.1 (M+H)+.
    • Example 274 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N-(4-methoxyphenyl)urea
  • The desired product was prepared by substituting Example 261A and 4-isocyanate-1-methoxybenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.72 (s, 3 H) 5.22 (s, 2 H) 6.88 (d, J=8.8 Hz, 2 H) 7.13 (dd, J=7.1, 0.7 Hz, 1 H) 7.38 (d, J=8.8 Hz, 2 H) 7.42 (d, J=8.5 Hz, 2 H) 7.48 (dd, J=8.5, 0.7 Hz, 1 H) 7.58 (dd, J=8.5, 7.5 Hz, 1 H) 7.62 (d, J=8.5 Hz, 2 H) 8.54 (s, 1 H) 8.79 (s, 1 H) MS (ESI(+)) m/e 375.1 (M+H)+.
    • Example 275 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]urea
  • A solution of Example 261A (45 mg, 0.2 mmol) and sodium isocyanate (26 mg, 0.4 mmol) in HOAc (0.5 mL) and H2O (0.5 mL) was stirred overnight at rt, then diluted with water. The precipitated solid was collected by filtration and recrystallized from THF/hexanes to give an offwhite solid (35 mg, 65%). 1H NMR (300 MHz, DMSO-D6) δ ppm 5.20 (s, 2 H) 5.92 (s, 2 H) 7.11 (dd, J=7.3, 0.9 Hz, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.46 (dd, J=8.5, 1.0 Hz, 1 H) 7.57 (d, J=8.5 Hz, 2 H) 7.57 (dd, J=8.1, 7.1 Hz, 1 H) 8.72 (s, 1 H) MS (ESI(+)) m/e 269.0 (M+H)+.
    • Example 276 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-nitrophenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-nitro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2 H) 7.15 (d, J=6.8 Hz, 1 H) 7.45-7.50 (m, 3 H) 7.57-7.62 (m, 2 H) 7.66 (d, J=8.5 Hz, 2 H) 7.75 (dd, J=7.8, 1.7 Hz, 1 H) 7.84 (dd, J=8.1, 2.4 Hz, 1 H) 8.59 (t, J=2.2 Hz, 1 H) 9.09 (s, 1 H) 9.34 (s, 1 H) MS (ESI(+)) m/e 390.0 (M+H)+.
    • Example 277 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N-(4-fluorophenyl)urea
  • The desired product was prepared by substituting Example 261 A and 1-fluoro-4-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2 H) 7.11-7.17 (m, 3 H) 7.40-7.51 (m, 5 H) 7.58 (dd, J=8.1, 7.1 Hz, 1 H) 7.63 (d, J=8.8 Hz, 2 H) 8.80 (s, 1 H) 8.90 (s, 1 H) MS (ESI(+)) m/e 363.0 (M+H)+.
    • Example 278 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-fluoro-2-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 6.99-7.06 (m, 1 H) 7.13-7.19 (m, 2 H) 7.25 (ddd, J=11.7, 8.1, 1.5 Hz, 1 H) 7.45 (d, J=8.8 Hz, 2 H) 7.49 (dd, J=8.5, 1.0 Hz, 1 H) 7.59 (dd, J=8.5, 7.5 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 8.17 (td, J=8.3, 1.7 Hz, 1 H) 8.62 (d, J=2.4 Hz, 1 H) 9.27 (s, 1 H) MS (ESI(+)) m/e 363.0 (M+H)+.
    • Example 279 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-chloro-2-fluoro-5-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.14 (dd, J=7.3, 0.9 Hz, I H) 7.34 (m, 2 H) 7.44 (d, J=8.5 Hz, 2 H) 7.48 (dd, J=8.3, 0.9 Hz, 1 H) 7.58 (dd, J=8.5, 7.1 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 7.81-7.84 (m, 1 H) 8.95 (s, 1 H) 8.97 (s, 1 H) MS (ESI(+)) m/e 397.0 (M+H)+.
    • Example 280 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methoxyphenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-chloro-5-isocyanato-2-methoxybenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.82 (s, 3 H) 5.22 (s, 2 H) 7.10 (d, J=9.2 Hz, 1 H) 7.14 (dd, J=7.1, 1.0 Hz, 1 H) 7.29 (dd, J=9.2, 2.5 Hz, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.48 (dd, J=8.3, 1.0 Hz, 1 H) 7.58 (dd, J=8.1, 7.1 Hz, 1 H) 7.62 (d, J=8.5 Hz, 2 H) 7.68 (d, J=2.5 Hz, 1 H) 8.71 (s, 1 H) 8.87 (s, 1 H) MS (ESI(+)) m/e 409.0 (M+H)+.
    • Example 281 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino)phenyl]urea
  • The desired product was prepared by substituting Example 261A and 4-dimethylamino-1-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.84 (s, 6 H) 5.21 (s, 2 H) 6.71 (d, J=9.2 Hz, 2 H) 7.13 (dd, J=7.1, 1.0 Hz, 1 H) 7.28 (d, J=9.2 Hz, 2 H) 7.41 (d, J=8.5 Hz, 2 H) 7.47 (dd, J=8.5, 1.0 Hz, 1 H) 7.58 (dd, J=8.5, 7.1 Hz, 1 H) 7.61 (d, J=8.5 Hz, 2 H) 8.36 (s, 1 H) 8.73 (s, 1 H) MS (ESI(+)) m/e 388.1 (M+H)+.
    • Example 282 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzodioxol-5-ylurea
  • The desired product was prepared by substituting Example 261A and 5-isocyanatobenzo[1,3]dioxole for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2 H) 5.98 (s, 2 H) 6.78 (dd, J=8.5, 2.0 Hz, 1 H) 6.84 (d, J=8.5 Hz, 1 H) 7.13 (dd, J=7.1, 1.0 Hz, 1 H) 7.22 (d, J=2.0 Hz, 1 H) 7.42 (d, J=8.5 Hz, 2 H) 7.48 (dd, J=8.1, 1.0 Hz, 1 H) 7.58 (dd, J=8.1, 7.5 Hz, 1 H) 7.61 (d, J=8.5 Hz, 2 H) 8.62 (s, 1 H) 8.80 (s, 1 H) MS (ESI(+)) m/e 389.0 (M+H)+.
    • Example 283 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl]urea
  • The desired product was prepared by substituting Example 261A and 4-isocyanate-1-(trifluoromethoxy)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.14 (dd, J=7.1, 1.0 Hz, 1 H) 7.30 (d, J=8.8 Hz, 2 H) 7.44 (d, J=8.5 Hz, 2 H) 7.48 (dd, J=8.5, 0.7 Hz, 1 H) 7.59 (dd, J=8.3, 7.3 Hz, 1 H) 7.59 (d, J=8.8 Hz, 2 H) 7.63 (d, J=8.5 Hz, 2 H) 8.93 (s, 1 H) 8.96 (s, 1 H) MS (ESI(-)) m/e 426.9 (M-H)-.
    • Example 284 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethoxy)phenyl]urea
  • The desired product was prepared by substituting Example 261A and 2-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.23 (s, 2 H) 7.11 (td, J=7.6, 2.0 Hz, 1 M 7.15 (d, J=7.1 Hz, 1 H) 7.36 (td, J=8.1, 1.4 Hz, 1 H) 7.39 (ddd, J=6.6, 3.1, 1.5 Hz, 1 H) 7.44-7.50 (m, 3 H) 7.59 (dd, J=8.5, 7.1 Hz, 1 H) 7.65 (d, J=8.5 Hz, 2 H) 8.28 (dd, J=8.3, 1.5 Hz, 1 H) 8.55 (s, 1 H) 9.48 (s, 1 H) MS (ESI(+)) m/e 429.0 (M+H)+.
    • Example 285 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 261A and 1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 7.15 (dd, J=7.1, 1.0 Hz, 1 H) 7.45-7.51 (m, 3 H) 7.59 (dd, J=8.5, 7.1 Hz, 1 H) 7.65-7.69 (m, 3 H) 8.16 (s, 2 H) 9.20 (s, 1 H) 9.47 (s, 1 H) MS (ESI(+)) m/e 481.0 (M+H)+.
    • Example 286 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methylphenyl)urea
  • The desired product was prepared by substituting Example 261A and 1-chloro-5-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3 H) 5.22 (s, 2 H) 7.14 (dd, J=7.1, 1.0 Hz, 1 H) 7.21 (dd, J=8.5, 2.0 Hz, 1 H) 7.26 (d, J=8.5 Hz, 1 H) 7.44 (d, J=8.8 Hz, 2 H) 7.48 (dd, J=8.5, 0.7 Hz, 1 H) 7.58 (dd, J=8.5, 7.5 Hz, 1 H) 7.63 (d, J=8.8 Hz, 2 H) 7.71 (d, J=2.0 Hz, 1 H) 8.84 (s, 1 H) 8.91 (s, 1 H) MS (ESI(+)) m/e 393.1 (M+H)+.
    • Example 287 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 100C and 1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.97 (s, 3 H) 5.21 (s, 2 H) 7.06 (d, J=8.1 Hz, 1 H) 7.17 (d, J=8.1 Hz, 1 H) 7.41 (d, J=8.5 Hz, 2 H) 7.63 (d, J=8.5 Hz, 2 H) 7.66 (s, 1 H) 8.16 (s, 2 H) 9.16 (s, 1 H) 9.45 (s, 1 H) MS (ESI(+)) m/e 511.0 (M+H)+.
    • Example 288 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl]urea
  • The desired product was prepared by substituting Example 100C and 4-isocyanate-1-(trifluoromethoxy)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3 H) 5.20 (s, 2 H) 7.04 (d, J=8.1 Hz, 1 H) 7.16 (d, J=8.1 Hz, 1 H) 7.30 (d, J=8.8 Hz, 2 H) 7.39 (d, J=8.5 Hz, 2 H) 7.58 (d, J=8.8 Hz, 2 H) 7.60 (d, J=8.5 Hz, 2 H) 8.89 (s, 1 H) 8.94 (s, 1 H) MS (ESI(+)) m/e 459.0 (M+H)+.
    • Example 289 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 100C for Example 15G in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3 H) 5.21 (s, 2 H) 6.80 (td, J=8.5, 2.4 Hz, 1 H) 7.05 (d, J=7.8 Hz, 1 H) 7.12-7.18 (m, 2 H) 7.28-7.36 (m, 1 H) 7.39 (d, J=8.5 Hz, 2 H) 7.51 (dt, J=11.9, 2.2 Hz, 1 H) 7.60 (d, J=8.5 Hz, 2 H) 8.91 (s, 1 H) 8.96 (s, 1 H) MS (ESI(+)) m/e 393.0 (M+H)+.
    • Example 290 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea
  • The desired product was prepared by substituting Example 100C and 3-isocyanato-1-methoxybenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.74 (s, 3 H) 3.96 (s, 3 H) 5.21 (s, 2 H) 6.57 (dd, J=8.3, 2.5 Hz, 1 H) 6.95 (dd, J=7.8, 1.5 Hz, 1 H) 7.04 (d, J=7.8 Hz, 1 H) 7.15-7.22 (m, 3 H) 7.38 (d, J=8.5 Hz, 2 H) 7.59 (d, J=8.5 Hz, 2 H) 8.73 (s, 1 H) 8.82 (s, 1 H) MS (ESI(+)) m/e 405.0 (M+H)+.
    • Example 291 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)urea
  • The desired product was prepared by substituting Example 100C and 1,3-difluoro-5-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3 H) 5.20 (s, 2 H) 6.80 (tt, J=9.3, 2.4 Hz, 1 H) 7.05 (d, J=8.1 Hz, 1 H) 7.17 (d, J=8.1 Hz, 1 H) 7.19-7.26 (m, 2 H) 7.40 (d, J=8.5 Hz, 2 H) 7.60 (d, J=8.5 Hz, 2 H) 9.01 (s, 1 H) 9.14 (s, 1 H) MS (ESI(+)) m/e 411.1 (M+H)+.
    • Example 292 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3 H) 3.96 (s, 3 H) 5.20 (s, 2 H) 7.04 (d, J=8.1 Hz, 1 H) 7.09 (d, J=8.1 Hz, 2 H) 7.16 (d, J=8.1 Hz, 1 H) 7.35 (d, J=8.1 Hz, 2 H) 7.37 (d, J=8.5 Hz, 2 H) 7.58 (d, J=8.5 Hz, 2 H) 8.60 (s, 1 H) 8.78 (s, 1 H) MS (ESI(+)) m/e 389.1 (M+H)+.
    • Example 293 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3 H) 5.20 (s, 2 H) 7.05 (d, J=7.8 Hz, 1 H) 7.14-7.18 (m, 2 H) 7.25 (t, J=8.0 Hz, 1 H) 7.33 (ddd, J=8.0, 2.0, 1.2 Hz, 1 H) 7.39 (d, J=8.5 Hz, 2 H) 7.60 (d, J=8.5 Hz, 2 H) 7.88 (t, J=1.9 Hz, 1 H) 8.91 (s, 1 H) 8.92 (s, 1 H) MS (ESI(+)) m/e 451.0, 453.0 (M+H)+.
    • Example 294 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-isocyanato-3,5-dimethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6 H) 3.96 (s, 3 H) 5.20 (s, 2 H) 6.63 (s, 1 H) 7.04 (d, J=8.1 Hz, 1 H) 7.09 (s, 2 H) 7.16 (d, J=8.1 Hz, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.59 (d, J=8.5 Hz, 2 H) 8.55 (s, 1 H) 8.79 (s, 1 H) MS (ESI(+)) m/e 403.1 (M+H)+.
    • Example 295 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino)phenyl]urea
  • The desired product was prepared by substituting Example 100C and 4-dimethylamino-1-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.84 (s, 6 H) 3.96 (s, 3 H) 5.20 (s, 2 H) 6.71 (d, J=9.2 Hz, 2 H) 7.03 (d, J=8.1 Hz, 1 H) 7.16 (d, J=8.1 Hz, 1 H) 7.28 (d, J=9.2 Hz, 2 H) 7.35 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.35 (s, 1 H) 8.68 (s, 1 H) MS (ESI(+)) m/e 418.1 (M+H)+.
    • Example 296 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzodioxol-5-ylurea
  • The desired product was prepared by substituting Example 100C and 5-isocyanatobenzo[1,3]dioxole for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3 H) 5.20 (s, 2 H) 5.97 (s, 2 H) 6.78 (dd, J=8.5, 2.0 Hz, 1 H) 6.84 (d, J=8.5 Hz, 1 H) 7.04 (d, J=8.1 Hz, 1 H) 7.16 (d, J=8.1 Hz, 1 H) 7.22 (d, J=2.0 Hz, 1 H) 7.37 (d, J=8.5 Hz, 2 H) 7.57 (d, J=8.5 Hz, 2 H) 8.60 (s, 1 H) 8.76 (s, 1 H) MS (ESI(+)) m/e 419.1 (M+H)+.
    • Example 297 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea Example 297A 4-iodo-7-methyl-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 15C for 2-bromo-6-fluorobenzonitrile in Example 95A. MS (ESI(+)) m/e 274.8 (M+H)+.
    • Example 297B 4-(4-aminophenyl)-7-methyl-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 297A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 240.0 (M+H)+.
    • Example 297C N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 2.45 (s, 3 H) 5.20 (s, 2 H) 6.80 (d, J=7.5 Hz, 1 H) 7.03 (d, J=7.1 Hz, 1 H) 7.17 (t, J=7.8 Hz, 1 H) 7.25 (d, J=8.5 Hz, 1 H) 7.31 (s, 1 H) 7.38 (dd, J=7.5, 1.0 Hz, 1 H) 7.40 (d, J=8.5 Hz, 2 H) 7.61 (d, J=8.5 Hz, 2 H) 8.64 (s, 1 H) 8.83 (s, 1 H) MS (ESI(+)) m/e 373.1 (M+H)+.
    • Example 298 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.20 (s, 2 H) 7.02-7.05 (m, 2 H) 7.27-7.32 (m, 2 H) 7.37-7.44 (m, 3 H) 7.62 (d, J=8.8 Hz, 2 H) 7.73-7.74 (m, 1 H) 8.94 (s, 1 H) 8.95 (s, 1 H) MS (ESI(+)) m/e 393.0 (M+H)+.
    • Example 299 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 2.45 (s, 3 H) 5.20 (s, 2 H) 6.79-6.84 (m, 1 H) 7.04 (d, J=7.1 Hz, 1 H) 7.11 (dd, J=11.4, 8.3 Hz, 1 H) 7.37-7.43 (m, 3 H) 7.61 (d, J=8.5 Hz, 2 H) 8.00 (dd, J=7.6, 1.9 Hz, 1 H) 8.54 (d, J=2.4 Hz, 1 H) 9.24 (s, 1 H) MS (ESI(+)) m/e 391.1 (M+H)+.
    • Example 300 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 297B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.46 (s, 3 H) 5.20 (s, 2 H) 7.05 (d, J=7.5 Hz, 1 H) 7.38-7.45 (m, 4 H) 7.48-7.55 (m, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 8.64 (dd, J=7.3, 2.2 Hz, 1 H) 8.97 (s, 1 H) 9.37 (s, 1 H) MS (ESI(+)) m/e 445.0 (M+H)+.
    • Example 301 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 297B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.20 (s, 2 H) 7.04 (d, J=7.1 Hz, 1 H) 7.32 (d, J=7.8 Hz, 1 H) 7.38 (dd, J=7.3, 0.9 Hz, 1 H) 7.42 (d, J=8.5 Hz, 2 H) 7.53 (t, J=8.0 Hz, 1 H) 7.59-7.64 (m, 3 H) 8.04 (s, 1 H) 9.00 (s, 1 H) 9.13 (s, 1 H) MS (ESI(+)) m/e 427.0 (M+H)+.
    • Example 302 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-isocyanato-3,5-dimethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6 H) 2.45 (s, 3 H) 5.20 (s, 2 H) 6.63 (s, 1 H) 7.04 (d, J=7.5 Hz, 1 H) 7.09 (s, 2 H) 7.38 (dd, J=7.3, 0.9 Hz, 1 H) 7.40 (d, J=8.5 Hz, 2 H) 7.60 (d, J=8.5 Hz, 2 H) 8.56 (s, 1 H) 8.81 (s, 1 H) MS (ESI(+)) m/e 387.1 (M+H)+.
    • Example 303 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N-(3-ethylphenyl)urea
  • The desired product was prepared by substituting Example 297B and 3-ethyl-1-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (t, J=7.5 Hz, 3 H) 2.45 (s, 3 H) 2.58 (q, J=7.6 Hz, 2 H) 5.20 (s, 2 H) 6.84 (d, J=7.5 Hz, 1 H) 7.04 (d, J=7.5 Hz, 1 H) 7.19 (t, J=7.8 Hz, 1 H) 7.27 (ddd, J=8.1, 2.0, 1.4 Hz, 1 H) 7.33-7.35 (m, 1 H) 7.38 (dd, J=7.3, 0.9 Hz, 1 H) 7.40 (d, J=8.5 Hz, 2 H) 7.61 (d, J=8.5 Hz, 2 H) 8.66 (s, 1 H) 8.82 (s, 1 H) MS (ESI(+)) m/e 387.1 (M+H)+.
    • Example 304 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3 H) 2.45 (s, 3 H) 5.19 (s, 2 H) 7.03 (d, J=7.5 Hz, 1 H) 7.10 (d, J=8.5 Hz, 2 H) 7.34-7.41 (m, 5 H) 7.60 (d, J=8.5 Hz, 2 H) 8.61 (s, 1 H) 8.80 (s, 1 H) MS (ESI(+)) m/e 373.1 (M+H)+.
    • Example 305 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl]urea
  • The desired product was prepared by substituting Example 297B and 1-trifluoromethoxy-4-isocyanatobenzene for Example 15G and 1-ffuoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.20 (s, 2 H) 7.04 (d, J=7.5 Hz, 1 H) 7.30 (d, J=8.5 Hz, 2 H) 7.37-7.42 (m, 3 H) 7.57-7.63 (m, 4 H) 8.91 (s, 1 H) 8.95 (s, 1 H) MS (ESI(+)) m/e 443.0 (M+H)+.
    • Example 306 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-fluoro-5-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.17 (s, 3 H) 2.45 (s, 3 H) 5.20 (s, 2 H) 7.04 (d, J=7.5 Hz, 1 H) 7.05 (dd, J=8.1, 2.0 Hz, 1 H) 7.18 (t, J=8.7 Hz, 1 H) 7.37-7.39 (m, 1 H) 7.41 (d, J=8.5 Hz, 2 H) 7.46 (dd, J=12.6, 2.0 Hz, 1 H) 7.60 (d, J=8.5 Hz, 2 H) 8.84 (s, 1 H) 8.88 (s, 1 H) MS (ESI(+)) m/e 391.1 (M+H)+.
    • Example 307 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-methoxy-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 3.74 (s, 3 H) 5.20 (s, 2 H) 6.57 (dd, J=8.1, 2.4 Hz, 1 H) 6.95 (dd, J=7.6, 1.5 Hz, 1 H) 7.04 (d, J=7.5 Hz, 1 H) 7.16-7.22 (m, 2 H) 7.37-7.43 (m, 3 H) 7.61 (d, J=8.5 Hz, 2 H) 8.74 (s, 1 H) 8.84 (s, 1 H) MS (ESI(+)) m/e 389.0 (M+H)+.
    • Example 308 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared by substituting Example 297B and isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.20 (s, 2 H) 6.98 (tt, J=7.1, 1.4 Hz, 1 H) 7.04 (d, J=7.5 Hz, 1 H) 7.27-7.32 (m, 2 H) 7.38 (dd, J=7.5, 1.0 Hz, 1 H) 7.40 (d, J=8.8 Hz, 2 H) 7.48 (dd, J=8.8, 1.0 Hz, 2 H) 7.61 (d, J=8.8 Hz, 2 H) 8.72 (s, 1 H) 8.85 (s, 1 H) MS (ESI(+)) m/e 359.0(M+H)+.
    • Example 309 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 297B and 1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.20 (s, 2 H) 7.05 (d, J=7.1 Hz, 1 H) 7.39 (dd, J=7.5, 0.7 Hz, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.63-7.66 (m, 3 H) 8.16 (s, 2 H) 9.18 (s, 1 H) 9.45 (s, 1 H) MS (ESI(+)) m/e 495.0 (M+H)+.
    • Example 310 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 297B and 1-promo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.20 (s, 2 H) 7.04 (d, J=7.1 Hz, 1 H) 7.16 (ddd, J=7.8, 1.9, 1.2 Hz, 1 H) 7.25 (t, J=8.0 Hz, 1 H) 7.33 (ddd, J=8.0, 2.0, 1.2 Hz, 1 H) 7.38 (m, J=7.5, 1.0 Hz, 1 H) 7.41 (d, J=8.5 Hz, 2 H) 7.61 (d, J=8.5 Hz, 2 H) 7.88 (t, J=1.9 Hz, 1 H) 8.93 (app. s., 2 H) MS (ESI(+)) m/e 436.9, 438.9 (M+H)+.
    • Example 311 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
  • The desired product was prepared by substituting Example 297B for Example 15G in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3 H) 5.19 (s, 2 H) 6.80 (tdd, J=8.5, 2.7, 1.0 Hz, 1 H) 7.04 (d, J=7.5 Hz, 1 H) 7.14 (ddd, J=8.2, 2.0, 0.7 Hz, 1 H) 7.32 (td, J=8.2, 7.0 Hz, 1 H) 7.37-7.44 (m, 3 H) 7.51 (dt, J=12.0, 2.3 Hz, 1 H) 7.61 (d, J=8.5 Hz, 2 H) 8.92 (s, 1 H) 8.96 (s, 1 H) MS (ESI(+)) m/e 377.1 (M+H)+.
    • Example 312 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 100C and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3 H) 5.20 (s, 2 H) 7.05 (d, J=8.1 Hz, 1 H) 7.16 (d, J=8.1 Hz, 1 H) 7.39 (d, J=8.5 Hz, 2 H) 7.45 (t, J=9.8 Hz, 1 H) 7.61 (d, J=8.5 Hz, 2 H) 7.64-7.69 (m, 1 H) 8.02 (dd, J=6.4, 2.7 Hz, 1 H) 8.97 (s, 1 H) 9.09 (s, 1 H) MS (ESI(+)) m/e 461.0 (M+H)+.
    • Example 313 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 100C and 1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J=2.0 Hz, 3 H) 3.96 (s, 3 H) 5.20 (s, 2 H) 7.03-7.09 (m, 2 H) 7.16 (d, J=8.1 Hz, 1 H) 7.27 (ddd, J=8.5, 4.1, 3.0 Hz, 1 H) 7.35-7.39 (m, 3 H) 7.59 (d, J=8.5 Hz, 2 H) 8.66 (s, 1 H) 8.81 (s, 1 H) MS (ESI(+)) m/e 407.1 (M+H)+.
    • Example 314 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea Example 314A 7-fluoro-4-iodo-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 26A for 2-bromo-6-fluorobenzonitrile in Example 95A. MS (ESI(+)) m/e 278.8 (M+H)+.
    • Example 314B 4-(4-aminophenyl)-7-fluoro-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 314A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 244.0 (M+H)+.
    • Example 314C N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 314B and 1-isocyanate-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.38 (s, 2 H) 7.12 (dd, J=8.3, 3.9 Hz, 1 H) 7.33 (d, J=7.8 Hz, 1 H) 7.43 (d, J=8.8 Hz, 2 H) 7.52 (dd, J=10.9, 8.1 Hz, 1 H) 7.53 (t, J=7.8 Hz, 1 H) 7.59-7.65 (m, 3 H) 8.04 (s, 1 H) 9.00 (s, 1 H) 9.12 (s, 1 H) MS (ESI(+)) m/e 431.0 (M+H)+.
    • Example 315 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 314B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.38 (s, 2 H) 7.03 (dt, J=6.4, 2.2 Hz, 1 H) 7.12 (dd, J=8.1, 4.1 Hz,1 1 H) 7.27-7.35 (m, 2 H) 7.42 (d, J=8.5 Hz, 2 H) 7.52 (dd, J=10.9, 8.1 Hz, 1 H) 7.62 (d, J=8.5 Hz, 2 H) 7.72-7.74 (m, 1 H) 8.95 (s, 1 H) 8.96 (s, 1 H) MS (ESI(+)) m/e 397.0 (M+H)+.
    • Example 316 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 314B and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.37 (s, 2 H) 7.12 (dd, J=8.1, 4.1 Hz, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.43 (d, J=9.2 Hz, 1 H) 7.52 (dd, J=10.9, 8.1 Hz, 1 H) 7.63 (d, J=8.5 Hz, 2 H) 7.64-7.69 (m, 1 H) 8.02 (dd, J=.4, 2.7 Hz, 1 H) 9.01 (s, 1 H) 9.10 (s, 1 H) MS (ESI(+)) m/e 449.0 (M+H)+.
    • Example 317 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 314B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 5.38 (s, 2 H) 6.81 (d, J=7.5 Hz, 1 H) 7.11 (dd, J=8.1, 4.1 Hz, 1 H) 7.17 (t, J=7.8 Hz, 1 H) 7.25 (d, J=8.5 Hz, 1 H) 7.32 (s, 1 H) 7.41 (d, J=8.5 Hz, 2 H) 7.51 (dd, J=10.9, 8.1 Hz, 1 H) 7.62 J=8.5 Hz, 2 H) 8.65 (s, 1 H) 8.85 (s, 1 H) MS (ESI(+)) m/e 377.1 (M+H)+.
    • Example 318 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 314B and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.38 (s, 2 H) 7.12 (dd, J=8.3, 3.9 Hz, 1 H) 7.38-7.55 (m, 5 H) 7.64 (d, J=8.8 Hz, 2 H) 8.64 (dd, J=7.3, 2.2 Hz, 1 H) 8.97 (d, J=3.1 Hz, 1 H) 9.37 (s, 1 H) MS (ESI(+)) m/e 449.0 (M+H)+.
    • Example 319 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 314B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 5.38 (s, 2 H) 6.79-6.84 (m, 1 H) 7.08-7.15 (m, 2 H) 7.43 (d, J=8.5 Hz, 2 H) 7.52 (dd, J=10.9, 8.1 Hz, 1 H) 7.62 (d, J=8.5 Hz, 2 H) 8.00 (dd, J=7.6, 1.9 Hz, 1 H) 8.55 (d, J=2.4 Hz, 1 H) 9.25 (s, 1 H) MS (ESI(+)) m/e 395.0 (M+H)+.
    • Example 320 N-{4-(3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl)phenyl}-N'-(2-fluoro-5-(trifluoromethyl)phenyl]urea Example 320A 6-bromo-2-fluoro-3-(trifluoromethoxy)benzonitrile
  • The desired product was prepared by substituting 4-bromo-2-fluoro-1-trifluoromethoxy-benzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C. MS (ESI(-)) m/e 282 (M-H)-.
    • Example 320B 4-bromo-7-(trifluoromethoxy)-1,2-benzisoxazol-3-amine
  • A solution of propan-2-one oxime (810 mg, 1. mmol) in THF (50 mL) was treated with potassium tert-butoxide (1.23 g) stirred at r.t for 30 min, then treated with example 320A (2.84 g, 10 mmol). The reaction mixture was stirred at r.t. for 30 min, then partitioned between EtOAc and water. The organic extract was washed with brine, dried (MgSO4) and concentrated. The residue was dissolved in ethanol (20 mL), treated with 5% HCl (20 mL) and heated at reflux for 2h. The reaction was allowed to cool to r.t the concentrated to half its volume resulting in a precipitate which was collected via filtration. The crude solid was purified via silica gel chromatography eluting with 0 to 10% EtOAc- hexanes to give 0.95 g of example 320B. MS (ESI(+)) m/e 297, 299 (M+H)+.
    • Example 320C 4-(4-aminophenyl)-7-(trifluoromethoxy)-1,2-benzisoxazol-3-amine
  • The desired product was prepared by substituting Example 320B for Example 15H in Example 15G. MS (ESI(+)) m/e 310 (M+H)+.
    • Example 320D N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 320C and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.44 (s, 2H), 7.22 (d, J=7.80 Hz, 1H), 7.35-7.46 (m, 1H), 7.46-7.52 (m, 3H), 7.62-7.72(m, 3H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.98 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS(ESI(+)) m/e 515(M+H)+.
    • Example 321 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 320C and 1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.44 (s, 2H), 7.22 (d, J=8.14 Hz, 1H), 7.33 (d, J=7.80 Hz, 1H), 7.45-7.72 (m, 7H), 8.04 (s, 1H), 9.03 (s, 1H), 9.13 (s, 1H); MS(ESI(+)) m/e 497(M+H)+.
    • Example 322 N- {4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]-phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 320C and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 5.44 (s, 2H), 6.75-6.90 (m, 1H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.21 (d, J=8.14 Hz, 1H), 7.47 (d, J=8.82 Hz, 2H), 7.55-7.75 (m, 3H), 8.00 (dd, J=7.97, 1.86 Hz, 1H), 8.56 (d, J=2.71 Hz, 1H), 9.28 (s, 1H); MS(ESI(+)) m/e 461 (M+H)+.
    • Example 323 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 320C and 3-chloro-1-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.43 (s, 2H), 7.95-7.06 (m, 1H), 7.21 (d, J=8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.47 (d, J=8.48 Hz, 2H), 7.6-7.9 (m, 4H), 8.97 (s, 1H), 8.99 (s, 1H); MS(ESI(+)) m/e 463(M+H)+.
    • Example 324 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-bromophenyl)urea
  • The desired product was prepared by substituting Example 320C and 3-bromo-1-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatoberazene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.43 (s, 2H), 7.10-7.37 (m, 4H), 7.47 (d, J=8.82 Hz, 2H), 7.60-7.72 (m, 3H), 7.88 (t, J=2.03 Hz, 1H), 8.96 (s, 1H), 8.99 (s, 1H); MS(ESI(+)) m/e 507(M+H)+.
    • Example 325 N-{3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 320C and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.43 (s, 2H), 7.21 (d, J=8.14 Hz, 1H), 7.40-7.52 (m, J=9.15, 9.15 Hz, 3H), 7.60-7.75 (m, 4H), 7.90-5.10 (dd, J=6.44, 2.71 Hz, 1H), 9.04 (s, 1H), 9.12 (s, 1H); MS(ESI(+)) m/e 515(M+H)+.
    • Example 326 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 320C and I-fluoro-4-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.23 (s, 3H), 5.43 (s, 2H), 7.06 (t, J=9.16 Hz, 1H), 7.21 (d, J=8.14 Hz, 1H), 7.25-7.40 (m, 2H), 7.45 (d, J=8.48 Hz, 2H), 7.58-7,78 (m, 3H), 8.69 (s, 1H), 8.88 (s, 1H); MS(ESI(+)) m/e 461(M+H)+.
    • Example 327 N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea Example 327A 2-(benzylthio)-6-iodobenzonitrile
  • A suspension of potassium tert-butoxide (1.12 g, 10.0 mmol) and phenylmethanethiol (1.24 g,10 mmol) in THF (30 mL) at room temperature was stirred for 10 minutes before treating with 2-fluoro-6-iodo-benzonitrile (2.47 g, 10 mmol). The solution was stirred for 1 hour at room temperature, poured into a saturated ammonium chloride solution and filtered. The filter cake was recrystallized from hexanes to provide 2.41 g (53% yield) of the desired product. MS(ESI(-)) m/e 350.0 (M-H)-.
    • Example 327B 4-iodo-1,2-benzisothiazol-3-amine
  • Example 327A (2.5 g, 7.1 mmol) was treated with sulfuryl chloride (1.0 M in dichloromethane, 3.5 mL, 35.5 mmol), stirred at room temperature for 2 hours and concentrated. The residue was dissolved in minimal THF, treated with ammonia (7.0 M in methanol, 10 mL), stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The combine organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The residue was triturated from ethyl acetate/hexanes to provide 1.2 g (61% yield) of the desired product. MS(ESI(-)) m/e 274.8,276.7 (M-H)-.
    • Example 327C N-[4-(3-amino-1,2-benzisothiaxol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
  • The desired product was prepared by substituting 1-isocyanato-3,5-dimethylbenzene for 1-isocyanato-3-methylbenzene, in example 1B and Example 327B for example 1A in example 1C. In addition PdCl2.dppf.CH2Cl2 was used in place of Pd(PPh3)4. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6H), 5.45 (s, 2H), 6.63 (s, 1H), 7.09 (s, 2H), 7.35 (d, J=8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.97 (d, J=8.14 Hz, 1H), 8.59 (s, 1H), 8.85 (s, 2H); MS(ESI(+)) m/e 389.0 (M+H)+.
    • Example 328 N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting 3-chloro-1-isocyanatobenzene for 1-isocyanato-3-methylbenzene, in example 1B and Example 327B for example 1A in example 1C. In addition PdCl2.dppf.CH2Cl2 was used in place of Pd(PPh3)4. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.45 (s, 2H), 7.01-7.10 (m, 1H), 7.17 (d, J=7.80 Hz, 1H), 7.30-7.40 (m, 3H), 7.50-7.65 (m, 4H), 7.70-7.80 (m, 1H), 7.97 (dd, J=7.97, 0.85 Hz, 1H), 9.00 (s, 2H); MS(ESI(+)) m/e 395.0 (M+H)+.
    • Example 329 N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzen for 1-isocyanato-3-methylbenzene, in example 1B and Example 327B for example 1A in example 1C. In addition PdCl2.dppf.CH2Cl2 was used in place of Pd(PPh3)4. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) ,5.45(s, 2H) 6.78-6.88 (m,1H) 7.05-7.25 (m, 2H), 7.37 (d, J=8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.90-8.10 (m, 2H), 8.56 (d, J=2.37 Hz, 1H), 9.28 (s, 1H); MS(ESI(+)) m/e 393.0 (M+H)+.
    • Example 330 N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 327B for example 1A in example 1C. In addition PdCl2.dppf.CH2Cl2 was used in place of Pd(PPh3)4. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H), 5.45 (s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.20-7.40 (m, 3H), 7.48-7.56 (m, 6H), 7.97 (d, J=8.14 Hz, 1H), 8.67 (s, 1H), 8.87 (s, 1H); MS(ESI(+)) m/e 375.0 (M+H)+.
    • Example 331 N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanate-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzene, in example 1B and Example 327B for example 1A in example 1C. In addition PdCl2.dppf.CH2Cl2 was used in place of Pd(PPh3)4. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.45 (s, 2H), 7.17 (d, J=7.12 Hz, 1H), 7.25-7.45 (m, 3H), 7.50-7.60 (m, 5H), 7.97 (d, J=7.46 Hz, 1H), 8.04 (s, 1H), 9.02 (s, 1H), 9.14 (s, 1H); MS(ESI(+)) m/e 429 (M+H)+.
    • Example 332 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 332A 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
  • The desired product was prepared by substituting 4-bromo-2-fluoro-phenylamine for Example 149A in Example 149B. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.32 (s, 12 H) 5.56 (s, 2 H) 6.72 (dd, J=8.82, 7.80 Hz, 1 H) 7.13 (m, 1 H) 7.18 (dd, J=7.97, 1.19 Hz, 1 H).
    • Example 332B N-(2-fluoro-5-methylphenyl)-N'-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
  • The desired product was prepared by substituting Example 332A for 4-bromo-2-ethylaniline in Example 149A. MS(ESI(+)) m/e 389 (M+H)+.
    • Example 332C 7-fluoro-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 26A for Example 15E in Example 15F. MS (ESI(+)) m/e 278 (M+H)+.
    • Example 332D N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 332B and Example 332C for Example 1B and Example 1A, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 6.77-6.81 (m, 2H), 7.09-7.17 (m, 2H), 7.24 (dd, J=8.48, 2.03 Hz, 1H), 7.36 (dd, J=12.21, 2.03 Hz, 1H), 8.03 (dd, J=7.97, 2.20 Hz, 1H), 8.31 (t, J=8.48 Hz, 1H), 9.03 (d, J=2.37 Hz, 1H), 9.15 (d, J=2.37 Hz, 1H); MS (ESI(+) m/e 412 (M+H)+.
    • Example 333 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea Example 333A N-(3-chlonophenyl)-N'-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
  • The desired product was prepared by substituting Example 332A and 1-chloro-3-isocyanato-benzene for 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A. MS(ESI(+)) m/e 391 (M+H)+.
    • Example 333B N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 333A and Example 332C for Example 1B and Example 1A, respectively, in Example 1C. 1H NMR (300 MHz, DMSO-D6) δ ppm 6.79 (dd, J=7.80,4.07 Hz, 1H), 7.03-7.07 (m, 1H), 7.14 (dd, J=11.36, 7.97 Hz, 1H), 7.24-7.39 (m, 4H), 7.75 (t, J=2.03 Hz, 1H), 8.25 (t, J=8.48 Hz, 1H), 8.73 (d, J=2.37 Hz, 1H), 9.31 (s, 1H); MS (ESI(+) m/e 414 (M+H)+.
    • Example 334 N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluorophenyl)-N'-(2-fluoro-5-methylphenyl)urea Example 334A 2-fluoro-6-iodo-3-[(1-methylpiperidin-4-yl)methoxy]benzonitrile
  • The desired product was prepared by substituting 1-methyl-4-piperidinemethanol for 2-(4-morpholinyl)ethanol in Example 75A. MS(ESI(+)) m/e 375 (M+H)+.
    • Example 334B 4-iodo-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 334A for Example 15E in Example 15F. MS(ESI(+)) m/e 387 (M+H)+.
    • Example 334C N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluorophenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 334B and Example 5A for Example 1A and Example 1B in Example 1C. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.42-1.58 (m, 2H), 2.08-2.18 (m, 3H), 2.28 (s, 3H), 2.79 (d, J=4.75 Hz, 3H), 2.91-3.11 (m, 2H), 3.51 (d, J=12.21 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.81-6.83 (m, 2H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.81 Hz, 2H), 8.00 (dd, J=7.97, 2.20 Hz, 1H), 8.53 (d, J=2.71 Hz, 1H), 9.19 (s, 1H); MS (ESI(+) m/e 503 (M+H)+.
    • Example 335 N-(4- {3-amino-7-[(1-methylpiperidin-4-yl)methoxy]1H-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 334B for Example 1A in Example 1C. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.41-1.53 (m, 2H), 2.07-2.18 (m, 3H), 2.29 (s, 3H), 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J=12.55 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.71 (d, J=7.46 Hz, 1H), 6.81 (m, 2H), 7.16 (m, 1H), 7.25 (d, J=8.14 Hz, 1H), 7.32 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.69 (s, 1H), 8.83 (s, 1H); MS (ESI(+) m/e 485 (M+H)+.
    • Example 336 N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxyl-1H-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 334B and 1-chloro-3-isocyanatobenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.41-1.53 (m, 2H), 2.07-2.18 (m, 3H), 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J=12.55 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.01-7.04 (m, 1H), 7.30-7.32 (m, 2H), 7.36 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 7.74 (m, 1H), 8.98 (s, 1H), 9.04 (s, 1H); MS (ESI(+) m/e 505 (M+H)+.
    • Example 337 N-(4-{3-amino-7-[(1-methylpipendin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 334B and 1-fluoro-2-methyl-4-isocyanatobenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.41-1.53 (m, 2H), 2.07-2.18 (m, 3H), 2.22(s, 3H) 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J=12.55 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.72 (d, J=7.46 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.05 (t, J=9.16 Hz, 1H), 7.25-7.40 (m, 2H), 7.34 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.82 Hz, 2H), 8.73 (s, 1H), 8.85 (s, 1H); MS (ESI(+) m/e 503 (M+H)+.
    • Example 338 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea Example 338A 2-fluoro-6-iodo-3-(3-pyridin-3-ylpropoxy)benzonitrile
  • The desired product was prepared by 3-pyridinepropanol for 2-(4-morpholinyl)ethanol in Example 75A. MS(ESI(+)) m/e 383 (M+H)+.
    • Example 338B 4-iodo-7-(3-pyridin-3-ylpropoxy)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 338A for Example 15E in Example 15F. MS(ESI(+)) m/e 395 (M+H)+.
    • Example 338C N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 338B and 1-chloro-3-isocyanatobenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1HNMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J=7.12 Hz, 2H), 4.16 (t, J=5.93 Hz, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.81 (d, J=7.80 Hz, 1H), 7.01-7.04 (m, 1H), 7.27-7.32 (m, 2H), 7.37 (d, J=8.81 Hz, 2H), 7.58 (d, J=8.81 Hz, 2H), 7.74 (t, J=2.03 Hz, 1H), 7.83 (dd, J=7.80, 5.42 Hz, 1H), 8.32 (d, J=7.80 Hz, 1H), 8.69 (d, J=4.07 Hz, 1H), 8.77 (d, J=2.03 Hz, 1H), 8.97 (s, 1H), 9.03 (s, 1H); MS (ESI(+) m/e 513 (M+H)+.
    • Example 339 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 338B for Example 1A in Example 1C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.22 (m, 2H), 2.29 (s, 3H), 3.05 (t, J=7.12 Hz, 2H), 4.16 (t, J=5.93 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.79-6.82 (m, 2H), 7.16 (m, 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.35 (d, J=8.81 Hz, 2H), 7.57 (d, J=8.81 Hz, 2H), 7.83 (dd, J=7.80, 5.42 Hz, 1H), 8.31 (d, J=8.14 Hz, 1H), 8.69 (m, 2H), 8.77 (d, J=1.69 Hz, 1H), 8.82 (s, 1H); MS (ESI(+) m/e 493 (M+H)+.
    • Example 340 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 338B and 1-fluoro-4-isocyanato)-2-(trifluromethyl)benzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.07-2.19 (m, 2H), 3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=5.93 Hz, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.82 Hz, 2H), 7.45 (t, J=9.16 Hz, 1H), 7.58 (d, J=8.48 Hz, 2H), 7.66 (m, 1H), 7.78 (dd, J=7.80, 5.42 Hz, 1H), 8.04 (dd, J=6.78, 2.71 Hz, 1H), 8.25 (d, J=8.14 Hz, 1H), 8.66 (d, J=4.41 Hz, 1H), 8.74 (d, J=1.70 Hz, 1H), 9.00 (s,1H), 9.16 (s, 1H); MS (ESI(+) m/e 565 (M+H)+.
    • Example 341 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(4-fluoro-3 - methylphenyl)urea
  • The desired product was prepared by substituting Example 338B and 1-fluoro-4-isocyanato-2-methylbenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.22 (m, 2H), 2.22 (s, 3H), 3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=6.10 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.05 (t, J=9.16 Hz, 1H), 7.19-7.40 (m, 4H), 7.56 (d, J=8.48 Hz, 2H), 7.82 (dd, J=7.97, 5.26 Hz, 1H), 8.30 (d, J=7.12 Hz, 1H), 8.69 (dd, J=5.43, 1.36 Hz, 1H), 8.73 (s, 1H), 8.76 (d, J=1.70 Hz, 1H), 8.85 (s, 1H); MS (ESI(+) m/e 511 (M+H)+.
    • Example 342 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chloro-4-fluorophenyl)urea
  • The desired product was prepared by substituting Example 338B and 1-fluoro-2-chloro-4-isocyanatobenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=5.93 Hz, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz, 1H), 7.33-7.38 (m, 4H), 7.57 (d, J=8.48 Hz, 2H), 7.77-7.84 (m, 2H), 8.27 (d, J=7.80 Hz, 1H), 8.67 (dd, J=5.42, 1.36 Hz, 1H), 8.75 (d, J=1.70 Hz, 1H), 8.97 (s, 1H), 9.01 (s, 1H); MS (ESI(+) m/e 531 (M+H)+.
    • Example 343 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 338B and 1-isocyanato-3-(trifluoromethyl)benzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=6.10 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.81 (m, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H), 7.60 (m, 3H), 7.81 (dd, J=8.14, 5.42 Hz, 1H), 8.05 (s, 1H), 8.28 (d, J=8.14 Hz, 1H), 8.68 (dd, J=5.26, 1.19 Hz, 1H), 8.76 (d, J=1.70 Hz, 1H), 9.01 (s, 1H), 9.19 (s, 1H); MS (ESI(+) m/e 547 (M+H)+.
    • Example 344 N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea Example 344A 2-fluoro-6-iodo-3-(3-pyridin-4-ylpropoxy)benzonitrile
  • The desired product was prepared by 4-pyridinepropanol for 2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+) m/e 382.9 (M+H)+.
    • Example 344B 4-iodo-7-(3-pyridin-4-ylpropoxy)-1H-indazol-3-amine
  • The desired product was prepared by substituting Example 344A for Example 15E in Example 15F. MS (ESI(+) m/e 395 (M+H)+.
    • Example 344C N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 344B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.09-2.15 (m, 2H), 2.28 (s, 3H), 2.90 (t, J=7.12 Hz, 2H), 4.13 (t, J=6.10 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J=7.80 Hz, 1H), 6.75 (d, J=7.80 Hz, 1H), 6.78-6.82 (m, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.31 (d, J=6.10 Hz, 2H), 7.36 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.97, 2.20 Hz, 1H), 8.47 (d, J=5.76 Hz, 2H), 8.53 (d, J=2.71 Hz, 1H), 9.18 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 511 (M+H)+.
    • Example 345 N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 344B for Example 1A in Example 1C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.07-2.16 (m, 2H), 2.29 (s, 3H), 2.90 (m, 2H), 4.13 (t, J=5.93 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J=7.46 Hz, 1H), 6.75 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (d, J=8.14 Hz, 1H), 7.31 (dd, J=4.07, 1.70 Hz, 3H), 7.35 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.47 (d, J=6.10 Hz, 2H), 8.64 (s, 1H), 8.77 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 493 (M+H)+.
    • Example 346 N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 344B and 1-chloro-3-isocyanatobenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.13 (m, 2H), 4.13 (t, J=6.10 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J=7.80 Hz, 1H), 6.75 (m, 1H), 7.02 (m, 1H), 7.31 (m, J=6.10, 2.03 Hz, 5H), 7.36 (d, J=8.81 Hz, 2H), 7.56 (m, J=8.48 Hz, 3H), 7.73 (s, 1H), 8.47 (m, 2H), 8.90 (s, 1H), 8.97 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 513 (M+H)+.
    • Example 347 N-[4-(3-amino-1H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 347A N-(4-bromo-2-hydroxyphenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 2-Amino-5-bromo-phenol for 4-bromo-2-ethylaniline in example 149A. MS(ESI(+)) m/e 339 and 341 (M+H)+.
    • Example 347B N-[4-bromo-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • A solution of example 347A (68 mg, 0.2 mmol) in acetone (2 mL) was treated with K2CO3 (41 mg, 0.3 mmol) and MOM-Cl (0.023 mL, 0.3 mmol), stirred at reflux for 2h, then allowed to cool to room temperature and treated with water. The resulting suspension was filterd and the filter cake was dried to give 58 mg of example 347B. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3 H) 3.45 (s, 3 H) 5.32 (s, 2 H) 6.78-6.83 (m, 1 H) 7.12-7.15 (m, 2 H) 7.29 (d, J=2.37 Hz, 1 H) 7.98 (dd, J=7.97,1.86 Hz, 1 H) 8.13 (d, J=8.82 Hz, 1 H) 8.82 (s, 1H) 9.22 (d, J=1.70 Hz, 1H).
    • Example 347C N-[4-(3-amino-1H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared substituting example 347B for example 44A in example 44B. 1H NMR (300 MHz, DMSO-D6) d ppm 2.28 (s, 3 H) 3.47 (s, 3 H) 4.42 (s, 2 H) 5.37 (s, 2 H) 6.78-6.83 (m, 2 H) 7.08 (dd, J=8.3, 1.9 Hz, 1 H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.24 (d, J=2.0 Hz, 1 H) 7.26 (s, 1 H) 7.27 (d, J=2.7 Hz, 1 H) 8.04 (dd, J=8.1, 2.0 Hz, 1H) 8.29 (d, J=8.5 Hz, 1 H) 8.89 (s, 1 H) 9.26 (d, J=1.7 Hz, 1 H) 11.72 (s, 1H); MS (ESI(+)) m/e 436.2 (M+H)+.
    • Example 348 N-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 348A N-(4-bromo-2-tetrahydro-2H-pyran-2-ylphenyl) N'-(2-fluoro-5-methylphenyl)urea
  • A solution of example 347A (150 mg, 0.44 mmol) and dihydropyran (0.24 mL, 2.4 mmol) in CH2Cl2 (2 mL) was treated with TsOH (1 mg) stirred at room temperature for 1h then partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic extract was washed with brine, dried (MgSO4), concentrated and purified via silica gel chromatography eluting with 20% EtOAc-hexanes to give 190 mg of 348A.
    • Example 348B N-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting example 348A (190 mg, 0.4 mmol) for 44A in example 44B, then dissolving the crude product in methanol treating with one drop of 1N HCl and stirring at r.t for 12h. Purification via silica gel chromatography eluting with 5% methanol-methylene chloride gave 14 mg of 348B. 1H NMR (500 MHz, DMSO-D6) d ppm 2.28 (s, 3 H) 6.77-6.81 (m, 2 H) 6.85 (dd, J=8.4, 1.9 Hz, 1 H) 6.94 (d, J=2.2 Hz, 1 H) 7.09 (dd, J=11.2, 8.4 Hz, 1 H) 7.24-7.29 (m, 2 H) 8.02 (dd, J=7.8, 1.3 Hz, 1 H) 8.17 J=8.4 Hz, 1 H) 8.81 (s, 1 H) 9.19 (d, J=1.9 Hz, 1 H) 10.14 (s, 1 H) 11.74 (s, 1 H); MS (ESI(+)) m/e 391.7 (M+H)+.
    • Example 349 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(hydroxymethyl)phenyl]urea Example 349A N-(4-bromophenyl)-N'-[2-fluoro-5-(hydroxymethyl)phenyl]urea
  • A solution of (3-amino-4-fluoro-phenyl)-methanol (0.61g, 4.3 mmol) in CH2Cl2 (20 mL) was treated with 1-isocyanato-4-bromobenzene (0.85g, 4.3 mmol) stirred at room temperature overnight resulting in a thick suspension which was filtered to give 1.43 g of 349 as a off white solid. MS (ESI(-)) m/e 336.9, 338.9 (M-H)+.
    • Example 349B N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(hydroxymethyl)phenyl]urea
  • The desired product was prepared by substituting example 349A for 149A in examples 149B-C. 1H NMR (300 MHz, DMSO-D6) d ppm 4.33 (s, 2 H) 4.46 (d, J=5.8 Hz, 2 H) 5.22 (t, J=5.8 Hz, 1 H) 6.79 (dd, J=5.4, 2.4 Hz, 1 H) 6.95 (ddd, J=8.1, 4.8, 2.0 Hz, 1 H) 7.11-7.30 (m, 3 H) 7.41 (d, J=8.5 Hz, 2 H) 7.60 (d, J=8.5 Hz, 2 H) 8.16 (dd, J=7.8, 2.0 Hz, 1 H) 8.58 (d, J=2.4 Hz, 1 H) 9.21 (s, 1 H) 11.71 (s, 1 H); MS (ESI(+)) m/e 392.0 (M+H)+.
    • Example 350 N-[4-(3-amino-7-thien-3-yl-1H-indazol4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl] Example 350A 4-(4-aminophenyl)-7-thien-3-yl-1H-indazol-3-amine
  • The desired product was prepared substituting thiophene-3-boronic acid for pyridine-3-boronic acid in examples 243D-E, then following the procedure of example 352B. Rf=0.24 (EtOAc).
    • Example 350B N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 350A and 1-isocyanato-3-trifluoromethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) d ppm 6.92 (d, J=7.1 Hz, 1 H) 7.33 (d, J=7.5 Hz, 1 H) 7.44 (d, J=8.8 Hz, 2 H) 7.48-7.68 (m, 6 H) 7.73 (dd, J=4.8, 2.7 Hz, 1 H) 7.96 (d, J=2.4 Hz, 1 H) 8.05 (s, 1 H) 9.01 (s, 1 H) 9.15 (s, 1 H) 11.96 (s, I H); MS (ESI(+)) m/e 494.0 (M+H)+.
    • Example 351 N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 350A and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. 1H NMR (300 MHz, DMSO-D6) d ppm 2.29 (s, 3 H) 6.79-6.84 (m, 1 H) 6.89 (d, J=7.5 Hz, 1 H) 7.12 (dd, J=11.4, 8.3 Hz, 1 H) 7.44 (d, J=8.5 Hz, 2 H) 7.54 (d, J=7.1 Hz, 1 H) 7.57-7.64 (m, 3 H) 7.72 (dd, J=4.9, 2.9 Hz, 1 H) 7.95 (s, 1 H) 8.02 (d, J=6.8 Hz, 1 H) 8.55 (d, J=2.0 Hz, 1 H) 9.23 (s, 1H) 11.84 (s, 1 H); MS (ESI(+)) m/e 458.1 (M+H)+.
    • Example 352 N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea Example 352A 4-(4-nitrophenyl)-7-pyridin-4-yl-1H-indazol-3-amine
  • The desired product was prepared by substituting pyridine-4-boronic acid for pyridine-3-boronic acid in examples 243D-E. Unlike example 243E only a small amount (ca. 20%) of the reduced product 352A was obtained. MS (ESI(+)) m/e 332 (M+H)+.
    • Example 352B 4-(4-aminophenyl)-7-pyridin-4-yl-1H-indazol-3-amine
  • A mixture of 352A (370 mg, 1.1 mmol), iron (374 mg) and NH4Cl (60 mg, 1.1 mmol) in ethanol (20 mL), THF (10 mL) and water (4 mL) was heated at reflux for 5h, diluted with THF (20 mL), filtered through a pad of celite, washing with ethanol. The filtrate was concentrated and the residue was triturated from water to give 313 mg of 352A as a light yellow solid. MS (ESI(+)) m/e 302 (M+H)+.
    • Example 352C N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting Example 352B and 1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) d ppm 2.23 (d, J=2.0 Hz, 3 H) 7.02 (d, J=7.5 Hz, 1 H) 7.06 (t, J=9.2 Hz, 1 H) 7.29 (ddd, J=8.7, 4.3, 2.9 Hz, 1H) 7.39 (dd, J=7.1, 2.4 Hz, 1 H) 7.46 (d, J=8.8 Hz, 2 H) 7.64 (d, J=8.8 Hz, 2 H) 7.72 (d, J=7.5 Hz, 1 H) 8.22 (d, J=3.7 Hz, 2 H) 8.78 (s, 1 H) 8.85-8.92 (m, 2 H) 8.96 (s, 1H); MS (ESI(+)) m/e 453.3 (M+H)+.
    • Example 353 N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 352B and 1-isocyanato-3-trifluoromethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) d ppm 7.02 (d, J=7.1 Hz, 1 H) 7.33 (d, J=7.5 Hz, 1 H) 7.48 (d, J=8.5 Hz, 2 H) 7.53 (t, J=8.0 Hz, 1 H) 7.62 (d, J=8.5 Hz, 1 H) 7.67 (d, J=8.5 Hz, 2 H) 7.71 (d, J=7.8 Hz, 1 H) 8.05 (s, 1 H) 8.19 (d, J=2.4 Hz, 2 H) 8.87 (d, J=2.4 Hz, 2 H) 9.11 (s, 1 H) 9.23 (s, 1 H); MS (ESI(+)) m/e 489.1 (M+H)+.
    • Example 354 N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting Example 352B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) d ppm 7.00-7.05 (m, 2 H) 7.29-7.33 (m, 2 H) 7.47 (d, J=8.8 Hz, 2 H) 7.65 (d, J=8.8 Hz, 2 H) 7.70 (d, J=7.5 Hz, 1 H) 7.75 (dd, J=2.5, 1.2 Hz, 1 H) 8.17 (d, J=3.7 Hz, 2 H) 8.86 (d, J=3.7 Hz, 2 H) 9.08 (app. s, 2 H); MS (ESI(+)) m/e 455.2 (M+H)+.
    • Example 355 N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 352B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) d ppm 2.29 (s, 3 H) 6.80-6.85 (m, 1 H) 7.01 (d, J=7.5 Hz, 1 H) 7.12 (dd, J=11.4, 8.3 Hz, 1 H) 7.47 (d, J=8.8 Hz, 2 H) 7.64 (d, J=8.8 Hz, 2 H) 7.69 (d, J=7.5 Hz, 1 H) 8.01 (dd, J=8.0, 1.9 Hz, 1 H) 8.14-8.19 (m, 2 H) 8.57 (d, J=2.7 Hz, 1 H) 8.82-8.89 (m, 2 H) 9.28 (s, 1 H); MS (ESI(+)) m/e 453.3 (M+H)+.
    • Example 356 N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 352B and 1-fluoro-4-isocyanato-2-trifluoromethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) d ppm 4.45 (s, 2 H) 6.95 (d, J=7.5 Hz, 1 H) 7.42-7.47 (m, 1 H) 7.45 (d, J=8.5 Hz, 2 H) 7.50 (d, J=7.5 Hz, 1 H) 7.64 (d, J=8.5 Hz, 2 H) 7.64-7.69 (m, 1 H) 7.71 (d, J=6.1 Hz, 2 H) 8.03 (dd, J=6.6, 2.6 Hz, 1 H) 8.68 (d, J=6.1 Hz, 2 H) 8.99 (s, 1H) 9.11 (s, 1 H) 11.98 (s, 1 H); MS (ESI(+)) m/e 507.2 (M+H)+.
    • Example 357 N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(tifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 352B and 1-fluoro-2-isocyanato-4-trifluoromethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH2Cl2. 1H NMR (300 MHz, DMSO-D6) d ppm 7.01 (d, J=7.5 Hz, 1 H) 7.42-7.49 (m, 3 H) 7.65-7.71 (m, 4 H) 8.04 (dd, J=6.4, 2.7 Hz, 1H) 8.14-8.21 (m, 2 H) 8.82-8.90 (m, 2 H) 9.12 (s, 1 H) 9.23 (s, 1H); MS (ESI(+)) m/e 507.7 (M+H)+.
    • Example 358 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea Example 358A 5-fluoro-4-iodo-1H-indazol-3-amine
  • The desired product was prepared by substituting 2,5-difluoro-benzonitrile for example 243A in example 243B, then substituting the product for 2-fluoro-6-iodo-benzonitrile in example 1A. MS (ESI(+) m/e 278 (M+H)+.
    • Example 358B N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenl)urea
  • The desired product was prepared by substituting 1-bromo-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively and in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 7.15-7.38 (m, 7 H) 7.61 (d, J=8.8 Hz, 2 H) 7.88 (t, J=1.9 Hz, 1 H) 8.95 (s, 1 H) 8.95 (s, 1 H) 11.82 (s, I H); MS (ESI(+)) m/e 439.9, 441.9 (M+H)+.
    • Example 359 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
  • The desired product was prepared by substituting Example 358B for 1A in Examples 1C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 2.29 (s, 3 H) 4.19 (s, 2 H) 6.80 (d, J=7.5 Hz, 1 H) 7.14-7.30 (m, 4 H) 7.32 (s, 1 H) 7.35 (d, J=8.5 Hz, 2 H) 7.61 (d, J=8.5 Hz, 2 H) 8.65 (s, 1 H) 8.83 (s, 1 H) 11.74 (s, 1 H); MS (ESI(+)) m/e 376.1 (M+H)+.
    • Example 360 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-phenylurea
  • The desired product was prepared by substituting 1- isocyanatobenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively and in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 6.98 (t, J=7.3 Hz, 1 H) 7.21 (t, J=9.3 Hz, 1 H) 7.27-7.32 (m, 3 H) 7.36 (d, J=8.1 Hz, 2 H) 7.48 (d, J=7.8 Hz, 2 H) 7.61 (d, J=8.5 Hz, 2 H) 8.74 (s, 1 H) 8.86 (s, 1 H) 11.81 (s, 1 H).
    • Example 361 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively and in Examples 1B-C. 1H NMR (300 MHz, DMSO-D6) d ppm 7.21 (t, J=9.2 Hz, 1H) 7.29 (dd, J=9.2, 4.1 Hz, 1 H) 7.37-3.40 (m, 4 H) 7.63 (d, J=8.5 Hz, 2 H) 8.45-8.50 (m, 1H) 8.90 (d, J=2.4 Hz, 1 H) 9.32 (s, 1 H) 11.81 (br, s, 1 H); MS (ESI(+)) m/e 448.1 (M+H)+.
    • Example 362 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 358B and 5A for 1A and 1B, respectively in Examples I C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 2.28 (s, 3 H) 6.82 (ddd, J=8.5, 4.8, 2.0 Hz, 1 H) 7.12 (dd, J=11.5, 8.1 Hz, 1H) 7.25 (t, J=9.3 Hz, 1 H) 7.33 (dd, J=9.2, 4.1 Hz, 1 H) 7.38 (d, J=8.5 Hz, 2 H) 7.62 (d, J=8.5 Hz, 2 H) 8.01 (dd, J=7.8, 2.0 Hz, 1 H) 8.55 (d, J=2.4 Hz, 1 H) 9.26 (s, 1 H) 12.01 (br. s, 1 H); MS (ESI(+)) m/e 394.0 (M+H)+.
    • Example 363 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-isocyanato-3-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 7.22 (t, J=9.5 Hz, 1 H) 7.28-7.34 (m, 2 H) 7.38 (d, J=8.1 Hz, 2 H) 7.53 (t, J=8.0 Hz, 1 H) 7.59-7.65 (m, 3 H) 8.04 (s, 1 H) 9.01 (s, 1 H) 9.14 (s, 1 H) 11.85 (br. s, 1 H); MS (ESI(+)) m/e 430.0 (M+H)+.
    • Example 364 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting 1-fluoro-4-isocyanato-3-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 7.23 (t, J=9.5 Hz, 1 H) 7.32 (dd, J=9.2, 4.1 Hz, 1 H) 7.38 (d, J=8.1 Hz, 2 H) 7.45 (t, J=9.5 Hz, 1 H) 7.66 (m, 3 H) 8.03 (dd, J=6.4, 2.7 Hz, 1 H) 9.04 (s, 1 H) 9.15 (s, 1 H) 11.94 (br. s, 1 H); MS (ESI(+)) m/e 448.0 (M+H)+.
    • Example 365 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
  • The desired product was prepared by substituting 1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 7.02-7.05 (m, 1 H) 7.25 (t, J=9.5 Hz, 1 H) 7.29-7.35 (m, 3 H) 7.38 (d, J=8.5 Hz, 2 H) 7.62 (d, J=8.5 Hz, 2 H) 7.73-7.75 (m, 1 H) 9.00 (s, 1 H) 9.01 (s, 1 H) 12.01 (br. s, 1 H); MS (ESI(+)) m/e 396.0 (M+H)+.
    • Example 366 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea
  • The desired product was prepared by substituting 1-fluoro-4-isocyanato-3-methylbenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 2.22 (d, J=1.7 Hz, 3 H) 7.06 (t, J=9.2 Hz, 1 H) 7.21-7.40 (m, 6 H) 7.61 (d, J=8.5 Hz, 2 H) 8.71 (s, 1 H) 8.88 (s, 1 H) 12.01 (br. s, 1 H); MS (ESI(+)) m/e 396.0 (M+H)+.
    • Example 367 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl)urea
  • The desired product was prepared by substituting 1-fluoro-2-chloro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively in Examples 1B-C and purifying as in example 3. 1H NMR (300 MHz, DMSO-D6) d ppm 7.24 (t, J=9.5 Hz, 1 H) 7.30-7.39 (m, 5 H) 7.62 (d, J=8.8 Hz, 2 H) 7.82-7.85 (m, 1 H) 9.00 (s, 1 H) 9.01 (s, 1 H) 11.99 (br. s, 1 H); MS (ESI(+)) m/e 414.0 (M+H)+.
    • Example 368 N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting 3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile and 1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 1A-C. 1H NMR (300 MHz, DMSO-D6) d ppm 2.28 (s, 3 H) 6.73 (d, J=7.5 Hz, 1H) 6.79-6.84 (m, 1 H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.40 (d, J=8.8 Hz, 2 H) 7.51 (d, J=7.80 Hz, 1H) 7.60 (d, J=8.8 Hz, 2 H) 8.01 (dd, J=7.5, 2.0 Hz, 1 H) 8.54 (d, J=2.4 Hz, 1 H) 9.22 (s, 1 H) 12.08 (br. s, 1 H); MS (ESI(+)) m/e 453.9,455.9 (M+H)+.
    • Example 369 3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoic acid Example 369A 4-(4-aminophenyl)-1H-indazol-3-amine
  • The desired product was prepared by substituting 2-fluoro-6-benzonitrile for 15F in example 15G, then substituting the product for 2-fluoro-6-benzonitrile in example 1A. MS (ESI(+)) m/e 225 (M+H)+.
    • Example 369B tert-butyl 3-amino-4-(4-aminophenyl)-1H-indazole-1-carboxylate
  • A-78 C solution of 369A (100 mg, 0.45 mmol) in THF (6 mL) was treated with LDA (0.245 mL, 2M solution in heptane, 0.49 mmol), stirred at - 50 for 15 minutes, treated with solid (Boc)2O (98 mg, 0.45 mmol). The reaction was allowed to gradually warm up to room temperature over 2h, concentrated in vacuo and purified via silica gel chromatography eluting first with 75% EtOAc: hexanes then with 8% methanol : CH2Cl2 to give 62 mg of 369B. MS (ESI(+)) m/e 325 (M+H)+.
    • Example 369C methyl 3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoate
  • A 0 C solution of 3-Amino-4-fluoro-benzoic acid methyl ester (29 mg, 0.17 mmol) in THF (4 mL) was treated with triethyl amine (0.026 mL) and 4-nitrophenyl chloroformate (38 mg), stirred at 0 C for 45 min, then treated with a solution of example 396B (56 mg, 0.17 mmol) in THF (3 mL) followed by an additional 0.026 mL of Et3N. The resulting mixture was allowed to warm up to room temperature slowly, stirred overnight, diluted with water and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4) concentrated and purified via silica gel chromatography eluting with EtOAc to give 98 mg of 3-Amino-4-(4-[3-(2-fluoro-5-methoxycarbonyl-phenyl)-ureido]-phenyl)-indazole-1-carboxylic acid tert-butyl ester. This compound was dissolved in CH2Cl2 (2 mL), cooled to 0 C, treated with TFA (1 mL), stirred at 0 for 45 min then at room temperature for 1h. The reaction was quenched with sat. aq. NaHCO3 adjusting the pH to 8-9 then extracted with EtOAc (3x). The combined organics were washed with brine, dried (MgSO4), concentrated and purified via silica gel chromatography eluting with first EtOAc then 12% methanol:CH2Cl2 to give 30 mg of 369C as a white solid. MS (ESI(+)) m/e 420 (M+H)+.
    • Example 369D 3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoic acid
  • A soluion of 369C (20 mg, 0.05 mmol) in methanol (1 mL) was treated with a solution of NaOH 911 mg) in water (1 mL), stirred at reflux for 7h and concentrated. The residue was diluted with water, the pH was adjusted to pH of 3 with 1 N HCl, and the resulting solid was collected via filtration to give 17 mg of 369D. H NMR (300 MHz, DMSO-D6) d ppm 4.34 (br. s, 2 H) 6.79 (dd, J=5.3, 2.5 Hz, 1 H) 7.24-7.28 (m, 2 H) 7.34-7.43 (m, 3 H) 7.60-7.64 (m, 3 H) 8.77 (d, J=2.7 Hz, 1 H) 8.85 (dd, J=8.1, 2.0 Hz, 1 H) 9.27 (s, 1 H) 11.72 (br. s, 1 H) 13.00 (br. s, 1 H).
    • Example 370 N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 182A for 1A in Example 5B. MS (ESI(+)Q1MS m/z 376 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 6.78-6.84 (m, 1 H) 7.11 (dd, J=11.36, 8.31 Hz, 1 H) 7.33 (dd, J=8.65, 1.19 Hz, 1 H) 7.48 (s, 1 H) 7.57 (d, J=8.82 Hz, 2 H) 7.67 (d, J-8.82 Hz, 2 H) 7.84 (d, J=8.48 Hz, 1 H) 8.00 (dd, J=7.80, 2.37 Hz, 1 H) 8.51 (d, J=2.71 Hz, 1 H) 9.19 (s, 1 H)
    • Example 371 N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl} oxy)ethyl]methanesulfonamide
  • The desired product was prepared by substituting Example 178A for Example 15G in Example 15H. MS (ESI(+)Q1MS m/z 499 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 2.99 (s, 3 H) 3.44 (q, J=5.61 Hz, 2 H) 4.23 (t, J=5.61 Hz, 2 H) 6.72 (d, J=7.49 Hz, 1 H) 6.79 (td, J=8.58, 2.18 Hz, 1 H) 6.83 (d, J=7.80 Hz, 1 H) 7.13-7.17 (m, 2 H) 7.29-7.34 (m, 1 H) 7.37 (d, J=8.42 Hz, 2 H) 7.51 (dt, J=11.93, 2.30 Hz, 1 H) 7.57 (d, J=8.73 Hz, 2 H) 8.85 (s, 1 H) 8.94 (s, 1 H)
    • Example 372 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 248B and 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)Q1MS m/z 531 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.20 (m, 2 H) 2.86 (d, J=5.09 Hz, 6 H) 3.34-3.41 (m, 2 H) 4.22 (t, J=5.76 Hz, 2 H) 6.72 (d, J=7.46 Hz, 1 H) 6.81 (d, J= 7.80 Hz, 1 H) 7.36 (d, J=8.48 Hz, 2 H) 7.45 (t, J=9.83 Hz, 1 H) 7.58 (d, J=8.48 Hz, 2 H) 7.63-7.69 (m, 1 H) 8.04 (dd, J=6.44, 2.71 Hz, 1 H) 9.02 (s, 1 H) 9.18 (s, 1 H)
    • Example 373 N-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 373A 1-acetyl-4-iodo-1H-indazol-3-amine
  • A solution of example 1A (215 mg, 0.83 mmol), acetic anhydride (0.086 mL) and 18-crown-6 (438 mg) in CH2Cl2 (5 mL) was stirred at room temperature overnight, then partitioned between EtOAc and water. The organic extract was dried (MgSO4), concentrated and purified via silica gel chromatography eluting with 1 to 1 hexane: EtOAc to give 110 mg of 373A. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.53 (s, 3 H) 6.01 (s, 2 H) 7.26 (t, J= 7.46 Hz, 1H) 7.77 (d, J=7.46 Hz, 1 H) 8.31 (d, J=8.48 Hz, 1 H).
    • Example 373B N-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 373A for 1A in Example 5B. MS (ESI(-)Q1MS m/z 416 (M-H)-; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 2.55 (s, 3 H) 5.20 (s, 2 H) 6.79-6.84 (m, 1H) 7.12 (dd, J=11.53, 8.48 Hz, 1 H) 7.18 (d, J=7.46 Hz, 1 H) 7.42 (d, J=8.48 Hz, 2 H) 7.57-7.64 (m, 3 H) 8.00 (dd, J=7.63, 1.87 Hz, 1 H) 8.29 (d, J=8.14 Hz, 1 H) 8.56 (d, J=2.71 Hz, 1 H) 9.26 (s, 1 H)
    • Example 374 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(4-bromo-3-methylphenyl)urea
  • The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 1-bromo-4-isocyanato-2-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)): m/e 456 (M+H); 1H NMR (300 MHz, DMSO-D6) δ ppm 2.32 (s, 3 H) 6.74 (dd, J=7.80, 4.41 Hz, 1 H) 7.13 (dd, J=11.19, 7.80 Hz, 1 H) 7.27 (dd, J=8.65, 2.54 Hz, 1 H) 7.37 (d, J=8.48 Hz, 2 H) 7.44-7.49 (m, 2 H) 7.58 (d, J=8.48 Hz, 2 H) 8.80 (s, 1H) 8.87 (s, 1 H).
    • Example 375 N-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea Example 375A 2-(4-iodo-1-phenyl-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione
  • A mixture of 162A (940 mg), phenyl boronic acid (590 mg), cupric acetate (440 mg), triethylamine (0.674 mL) in CH2Cl2 (20 mL) was stirred at room temperature overnight, then concentrated. The residue was purified via silica gel chromatography eluting with 20% EtOAc in hexane to give 770 mg of 375A. MS (ESI(+)) m/e 466.1 (M+H)+.
    • Example 375B 4-iodo-1-phenyl-1H-indazol-3-amine
  • The desired product was prepared by substituting 375A for 162B in example 162C. MS (ESI(+)) m/e 336.1 (M+H)+.
    • Example 375C N-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N-(2-fluoro-5-methylphenyl)
  • The desired product was prepared by substituting Example 375B for 1A in Example 5B. MS (ESI(+)Q1MS m/z 452 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 4.75 (s, 2 H) 6.83 (m, 1 H) 6.97 (d, J=6.44 Hz, 1H) 7.12 (dd, J=11.53, 8.48 Hz, 1 H) 7.26 (t, J=7.29 Hz, 1 H) 7.43-7.47 (m, 3 H) 7.50-7.55 (m, 2 H) 7.61-7.74 (m, 5 H) 8.01 (dd, J=7.97, 2.20 Hz, 1 H) 8.57 (d, J=2.37 Hz, 1 H) 9.26 (s, 1 H)
    • Example 376 N-{4-[3-amino-7-(3-pyridin-3-ylpopoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-methylphenyl)urea
  • The desired product was prepared by substituting Example 338B and 1-fluoro-2-isocyanato-4-methylbenzene for Example 1A and 1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. MS (ESI(+)Q1MS m/z 511 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.14-2.18 (m, 2 H) 2.28 (s, 3 H) 3.01 (t, J=7.4 Hz, 2 H) 4.14 (t, J=6.10 Hz, 2 H) 6.70 (d, J=7.80 Hz, 1 H) 6.77-6.84 (m, 2 H) 7.11 (dd, J=11.36, 8.31 Hz, 1 H) 7.37 (d, J=8.82 Hz, 2 H) 7.56 (d, J=8.48 Hz, 2 H) 7.70-7.73 (m, 1 H) 8.01 (dd, J=7.97, 2.20 Hz, 1 H) 8.17 (d, J=9.49 Hz, 1 H) 8.52 (d, J=3.05 Hz, 1 H) 8.62 (d, J=5.09 Hz, 1 H) 8.70 (s, 1 H) 9.17 (s, 1 H).
    • Example 377 N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-phenylurea
  • The desired product was prepared by substituting Example 182A and N-phenyl)'N'-[4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for 1A and 5A respectively, in Example 5B. MS (ESI(+)Q1MS m/z 344 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 5.33 (s, 2 H) 6.97 (t, J=7.29 Hz, 1 H) 7.19 (dd, J=8.31, 1.19 Hz, 1 H) 7.28 (t, J=7.97 Hz, 2 H) 7.38 (s, 1 H) 7.48 (d, J=7.46 Hz, 2 H) 7.59 (m, 4 H) 7.72 (d, J=8.48 Hz, 1 H) 8.90 (s, 1H) 8.96 (s, 1H) 11.38 (s, 1 H)
    • Example 378 N-[4-(3-amino-1H-indazol-6-yl)phenyl-N'-[3-(trifluoromethyl)phenyl]urea
  • The desired product was prepared by substituting Example 182A and N-(3-trifluoromethylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for 1A and 5A respectively, in Example 5B. MS (ESI(+)QIMS m/z 412 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 7.33 (dd, J=7.97, 4.58 Hz, 2 H) 7.55-7.58 (m, 3 H) 7.58 (d, J=8.82 Hz, 2 H) 7.67 (d, J=8.82 Hz, 2 H) 7.85 (d, J=8.48 Hz, 1 H) 8.04 (s, 1 H) 8.95 (s, 1 H) 9.11 (s, 1 H).
    • Example 379 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-thien-3-ylurea
  • The desired product was prepared by substituting 3-isocyanato-thiophene for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.33 (s, 2 H) 6.78 (dd, J=5.59, 2.20 Hz, 1 H) 7.07 (dd, J=5.09,1.36 Hz, 1 H) 7.24 - 7.28 (m, 2 H) 7.29 - 7.33 (m, 1 H) 7.39 (d, J=8.48 Hz, 2 H) 7.45 (dd, J=5.09, 3.39 Hz, 1 H) 7.59 (d, J=8.48 Hz, 2 H) 8.78 (s, 1 H) 8.99 (s, 1 H) 11.70 (s, 1 H); MS (ESI (+)) m/e 350 (M+H)+.
    • Example 3 80 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-cyclopentylurea
  • The desired product was prepared by substituting isocyanato-cyclopentane for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 - 1.45 (m, 2 H) 1.47 - 1.71 (m, 4 H) 1.77 - 1.93 (m, 2 H) 3.89 - 4.00 (m, 1 H) 4.31 (s, 2 H) 6.21 (d, J=7.12 Hz, 1 H) 6.75 (dd, J=5.59, 2.20 Hz, 1 H) 7.22 - 7.27 (m, 2 H) 7.32 (d, J=8.48 Hz, 2 H) 7.50 (d, J=8.48 Hz, 2 H) 8.39 (s, 1 H) 11.68 (s, 1 H). MS (ESI (+)) m/e336 (M+H)+.

Claims (14)

  1. The compound of formula (II)
    Figure imgb0013
     or a therapeutically acceptable salt thereof, wherein
    X is selected from the group consisting of O and S;
    R1 and R2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl;
    R3 and R4 are independently selected from the group consisting of hydrogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy;
    L is selected from the group consisting of (CH2)mN(R7)C(O)N(R8)(CH2)n and CH2C(O)NR7, wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to the ring substituted with R3 and R4;
    R7 and R8 are independently selected from the group consising of hydrogen and alkyl;
    R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd;
    Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; and
    Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
    wherein
    the aryl is a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a-phenyl group,
    wherein said aryl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, (NRcRd)alkyl, and oxo;
    wherein the second aryl group, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl is optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;
    the heterocyclyl is a monocyclic, bicyclic, or tricyclic ring system wherein one or more rings is a four-, five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
    wherein said heterocyclyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, (NRcRd)alkyl, and oxo;
    wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl is further optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.
    The cycloalkyl is a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms,
    wherein said cycloalkyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo.
  2. The compound of claim 1 wherein X is O.
  3. The compound of claim 1 wherein L is CH2C(O)NR7.
  4. The compound of claim 1 wherein L is (CH2)mN(R7)C(O)N(R8)(CH2)n.
  5. The compound of claim 1 wherein X is O and L is (CH2)mN(R7)C(O)N(R8)(CH2)n.
  6. The compound of claim 5 selected from the group consisting of
    N- [4-(3 - ami no-1,2-benzisoxazol-4 -yl)phenyl] -N'-(3 -methylphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5.-methylphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
    N-{4-[3-amino-7-(4-morpholiny.lrnethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl] urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-yl]phenyl }-N'-(3-methylphenyl)urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]pheny}-N'-(2-fluoro-5-methylphenyl)urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3,5-dimethylphenyl)urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-phenoxyphenyl)urea;
    N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-bromophenyl)urea;
    N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl] urea;
    N-(4-{3-amin-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea;
    N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[2-fluoro-5-(trifluoromethyl)phenyl] urea;
    N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(3-methylphenyl)urea;
    N-[4-{3-amino-1,2-benzisoxazol-4-yl}phenyl]-N'-(3,5-dimethylphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea;
    N-[4-(3-amino-1,2-benzisoxazol4-yl)phenyl] -N-(4-methylphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-4-fluoro-3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methoxyphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-nitrophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methoxyphenyl)urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino)phenylJurea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethoxy)phenyl]urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N-[3,5-bis(trifluoromethyl)phenyl] urea;
    N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methylphenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl]urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino)phenyl]urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl] urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea;
    N-[4-(3-ammo-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
    N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea;
    N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-fluoro-1,2-benzisoxazol4-yl)phenyl]-N'-(3-chlorophenyl)urea;
    N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
    N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
    N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl] urea;
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N-(2-fluoro-5-methylphenyl)urea;
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea;
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-bromophenyl)urea;
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl }-N'-[4-fluoro-3-(trifluoromethyl)phenyl]urea; and
    N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl }-N'-(4-fluoro-3-methylphenyl)urea.
  7. The compound of claim 1 wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl.
  8. The compound of claim 1 wherein X is S and L is (CH2)mN(R7)C(O)N(R8)(CH2)n.
  9. The compound of claim 8 selected from the group consisting of
    N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea;
    N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
    N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
    N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; and
    N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea.
  10. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  11. Use of a compound of claim 1, or a therapeutically acceptable salt thereof for manufacturing a medicament for inhibiting a protein kinase in a patient in recognized need of such treatment wherein the compound is to be administered to the patient in a therapeutically acceptable amount.
  12. Use of a compound of claim 1, or a therapeutically acceptable salt thereof for manufacturing a medicament for treating cancer in a patient in recognized need of such treatment wherein the compound is to be administered to the patient in a therapeutically acceptable amount.
  13. The compound of claim 1 for use as a protein kinase inhibitor.
  14. The compound of claim 1 for use as an anti-cancer agent.
EP10164213A 2003-05-22 2004-05-21 Indazole, benzisoxazole, and benzisothiazole kinase inhibitors Expired - Lifetime EP2246333B1 (en)

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